Cancer Letters RSS feed: Articles in Press. CANCER LETTERS is an international journal that considers full-length articles and Mini Reviews in the broad area of basic and translational oncology. Additionally, Special Issues highlight topical areas in cancer research. Basic areas of interest to a broad readership of Cancer Letters include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal places emphasis on experimental therapeutics, particularly targeted therapies for personalized cancer medicine. Cancer Letters now offers online submission for authors. Please submit manuscripts at http://www.ees.elsevier.com/can and follow the instructions on the site. http://www.cancerletters.info//inpress?rss=yesElsevier Inc.en © 2012 Elsevier Ireland Ltd. All rights reserved. Cancer Letters0304-38352012-02-06 © 2012 Elsevier Ireland Ltd. All rights reserved. healthpermissions@elsevier.comhttp://www.cancerletters.info/article/PIIS0304383512000377/abstract?rss=yesAbstract: Renal cell carcinoma (RCC) is a highly malignant and often fatal disease of the kidney. Chmp1A is a member of the Endosomal Sorting Complex Required for Transport (ESCRT-III) family, and plays a role in the cytoplasm in sorting proteins to the multivesicular body (MVB). Chmp1A functions as a tumor suppressor gene and has been reported in pancreatic tumor cells. Here, we examined the expression level of Chmp1A in human RCC tissues and renal tumor cells by real-time quantitative RT-PCR and western blot. We found that the expression level of Chmp1A is significantly lower in RCC tissues and renal tumor cells compared with adjacent non-tumorous tissues and normal renal cells. Additionally, inhibition of Chmp1A expression by shRNA induced tumor formation in normal renal cells. However, inhibition of Chmp1A did not significantly affect tumor cell proliferation in vitro and tumor progression in vivo. Interestingly, overexpression of Chmp1A using a eukaryotic plasmid inhibited the proliferation of renal tumor cells in vitro and the growth of renal tumor in vivo. Thus, our results demonstrate that Chmp1A functions as a tumor suppressor gene in renal cells and may be a useful target for treatment of RCC.Chmp1A acts as a tumor suppressor gene that inhibits proliferation of renal cell carcinoma - Corrected ProofZhenqiang You, Yanfei Xin, Yan Liu, Junying Sun, Guoliang Zhou, Haiyan Gao, Pansheng Xu, Yunxiang Chen, Guochan Chen, Lijiang Zhang, Liqiang Gu, Zhiqin Chen, Bin Han, Yaoxian Xuan10.1016/j.canlet.2012.01.010Cancer Letters (2012)2012-02-06Cancer Letters2012-02-06http://www.cancerletters.info/article/PIIS0304383512000389/abstract?rss=yesAbstract: Valproic acid (VPA) has extensive effects on leukemic blasts through its inhibition of histone deacetylases. The main goal of this study was to identify the subgroup of patients who may benefit most from VPA treatment. We examined the significance of t(8;21) chromosomal aberration for VPA treatment response among acute myeloid leukemia (AML) patients by direct comparison of AML1/ETO-negative vs. positive leukemic cell-lines as well as bone marrow blasts from AML patients. In t(8;21) AML, leukemogenesis is supposed to be induced via aberrant recruitment of histone deacetylases. AML cell lines of different genotypes (Kasumi-1, Kasumi-6, MV4;11, K562) and diagnostic bone marrow samples from patients were treated with VPA. VPA induced apoptosis in AML1/ETO-positive and MLL–AF4-positive cells in a dose-dependent manner. Differentiation, as indicated by changes in immunophenotype, was observed only in AML1/ETO-positive cells. VPA increased the expression of AML1 target genes – PU.1, C/EBPa, BPI and IGFBP7 only in AML1/ETO-positive cells. This AML1/ETO-specific effect was confirmed also using patient blasts isolated at the time of diagnosis. AML1/ETO-positive leukemia shows specific mechanism of VPA residing from differentiation followed by apoptosis that is accompanied by an increase in the expression of repressed AML1 target genes. Our data suggest that AML1/ETO-positive patients might derive the greatest benefit from VPA treatment.Valproic acid triggers differentiation and apoptosis in AML1/ETO-positive leukemic cells specifically - Corrected ProofMichal Zapotocky, Ester Mejstrikova, Karel Smetana, Jan Stary, Jan Trka, Julia Starkova10.1016/j.canlet.2011.12.041Cancer Letters (2012)2012-02-06Cancer Letters2012-02-06http://www.cancerletters.info/article/PIIS0304383512000419/abstract?rss=yesAbstract: Although surgical resection with adjuvant chemotherapy and/or radiotherapy are used to treat breast tumors, normal tissue tolerance, development of metastases, and inherent tumor resistance to radiation or chemotherapy can hinder a successful outcome. We have developed a thermally responsive polypeptide, based on the sequence of Elastin-like polypeptide (ELP), that inhibits breast cancer cell proliferation by blocking the activity of the oncogenic protein c-Myc. Following systemic administration, the ELP – delivered c-Myc inhibitory peptide was targeted to tumors using focused hyperthermia, and significantly reduced tumor growth in an orthotopic mouse model of breast cancer. This work provides a new modality for targeted delivery of a specific oncogene inhibitory peptide, and this strategy may be expanded for delivery of other therapeutic peptides or small molecule drugs.A thermally targeted c-Myc inhibitory polypeptide inhibits breast tumor growth - Corrected ProofGene L. Bidwell, Eddie Perkins, Drazen Raucher10.1016/j.canlet.2011.12.042Cancer Letters (2012)2012-02-06Cancer Letters2012-02-06http://www.cancerletters.info/article/PIIS0304383512000456/abstract?rss=yesAbstract: Although pre-clinical and clinical studies on PARP1 inhibitors, alone and in combination with DNA-damaging agents, show promising results, further ways to improve and broaden the scope of application of this therapeutic approach are warranted. To this end, we have investigated the possibility of improving the response of BRCA1 mutant breast cancer cells to PARP1 inhibition by co-targeting the PI3K pathway. Human breast cancer cell lines with or without the expression of BRCA1 and/or PTEN were treated with PARP1 and PI3K inhibitors as single agents and in combination. PARP1 inhibition induced DNA damage conferring a G2/M arrest and decrease in viability, paralleled by the induction of apoptosis. PI3K inhibition alone caused a G1 arrest and decreased cell growth. Most importantly, sequential combination of PARP and PI3K inhibitors interacted synergistically to significantly decrease growth compared to PARP inhibition alone. Global transcriptional profiling revealed that this decrease in growth was associated with down-regulation of macromolecule biosynthesis and the induction of apoptosis. Taken together, these results suggest an improved treatment strategy for BRCA1-mutant and possibly also triple-negative breast cancers with similar molecular defects.Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition - Corrected ProofSiker Kimbung, Ewa Biskup, Ida Johansson, Kristina Aaltonen, Astrid Ottosson-Wadlund, Sofia Gruvberger-Saal, Heather Cunliffe, Bengt Fadeel, Niklas Loman, Pontus Berglund, Ingrid Hedenfalk10.1016/j.canlet.2012.01.015Cancer Letters (2012)2012-02-06Cancer Letters2012-02-06http://www.cancerletters.info/article/PIIS0304383512000274/abstract?rss=yesAbstract: To better understand the response of HCC to EGFR inhibition, we analyzed factors connected to the resistance of HCC cells against gefitinib. Sensitive HCC3 cells co-expressed EGFR and ErbB3 but lacked kinase-domain mutations in EGFR. Interestingly, expression of MVP was restricted to resistant cell lines, whereas ABCB1 and ABCC1 showed no association with gefitinib resistance. Moreover, ectopic MVP expression in HCC3 cells decreased gefitinib sensitivity, increased AKT phosphorylation and reduced the expression of inflammatory pathway-associated genes, whereas silencing of MVP in Hep3B and HepG2 cells increased sensitivity. These findings suggest MVP as a novel player in resistance against EGFR inhibition.The major vault protein mediates resistance to epidermal growth factor receptor inhibition in human hepatoma cells - Corrected ProofAnnemarie Losert, Daniela Lötsch, Andreas Lackner, Herwig Koppensteiner, Barbara Peter-Vörösmarty, Elisabeth Steiner, Klaus Holzmann, Thomas Grunt, Katharina Schmid, Brigitte Marian, Bettina Grasl-Kraupp, Rolf Schulte-Hermann, Georg Krupitza, Walter Berger, Michael Grusch10.1016/j.canlet.2012.01.002Cancer Letters (2012)2012-02-03Cancer Letters2012-02-03http://www.cancerletters.info/article/PIIS0304383512000286/abstract?rss=yesAbstract: The ability of DNA repair in a cell is vital to its genomic integrity and thus to the normal functioning of an organism. Phosphatase and tensin homolog (PTEN) is a well-established tumor suppressor gene that induces apoptosis and controls cell growth by inhibiting the PI3K/AKT pathway. In various human cancers, PTEN is frequently found to be mutated, deleted, or epigenetically silenced. Recent new findings have demonstrated that PTEN also plays a critical role in DNA damage repair and DNA damage response. This review summarizes the recent progress in the function of PTEN in DNA damage repair, especially in double strand break repair and nucleotide excision repair. In addition, we will discuss the role of PTEN in DNA damage response through its interaction with the Chk1 and p53 pathways. We will focus on the newly discovered mechanisms and the potential implications in cancer prevention and therapeutic intervention.PTEN in DNA damage repair - Corrected ProofMei Ming, Yu-Ying He10.1016/j.canlet.2012.01.003Cancer Letters (2012)2012-02-03Cancer Letters2012-02-03MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512000365/abstract?rss=yesAbstract: Gene therapy is an important means for the comprehensive treatment of pancreatic cancer. Challenges associated with gene therapy include control of vector security and effective genetic screening. In this paper, a CEA promoter-regulated oncolytic adenovirus vector was constructed. The reporter gene assay demonstrated that the viral vector was confirmed to have tumor-specific replication features. In vitro cytology studies showed that the CEA promoter regulated the proliferation of the adenovirus vector carrying the Hsp70 gene (AdCEAp-Hsp70), which significantly increased the expression levels of Hsp70 in the CEA-positive pancreatic cancer cells, resulting in an overall reduction in the survival of cancer cells. In the human pancreatic cancer Panc-1 xenograft model in immune deficient nude mice, the CEA promoter-regulated adenovirus AdCEAp-Hsp70 significantly inhibited tumor growth. In the rat pancreatic cancer DSL-6A/C1 xenograft model in rats, the viral proliferation and high expression levels of Hsp70 promoted the interstitial infiltration of CD4+, CD8+ and gamma/delta T cells into tumors, induced host secretion of the cytokines TGF-β, INF-γ, and IL-6 and had a dual anti-tumor effects that completely inhibited the growth of pancreatic cancer. The results demonstrated that the oncolytic adenovirus under the control of CEA promoter provides additional assurances regarding the safety and efficiency of cancer gene therapy. This gene therapy model improves anti-cancer efficiency and has broad applications and developmental prospects.CEA promoter-regulated oncolytic adenovirus-mediated Hsp70 expression in immune gene therapy for pancreatic cancer - Corrected ProofCan Xu, Yunliang Sun, Yunfeng Wang, Yan Yan, Zhengjie Shi, Lei Chen, Han Lin, Shunli Lü, Maoling Zhu, Changqing Su, Zhaoshen Li10.1016/j.canlet.2012.01.009Cancer Letters (2012)2012-02-03Cancer Letters2012-02-03http://www.cancerletters.info/article/PIIS0304383512000390/abstract?rss=yesAbstract: The epidermal growth factor receptor (EGFR) pathway is one of the most dysregulated molecular pathways in human cancers. Despite its well-established importance in tumor growth, progression and drug-resistant phenotype over the past several decades, targeted therapy designed to circumvent EGFR has yielded only modest clinical success in cancer patients, except those with non-small cell lung cancer (NSCLC) carrying EGFR activation mutations. However, almost all of these NSCLC patients eventually developed resistance to small molecule EGFR kinase inhibitors. These disappointing outcomes are, in part, due to the high complexity and the interactive nature of the EGFR signaling network. More recent compelling evidence further indicates that EGFR functionality can be dependent on its subcellular location. In this regard, EGFR undergoes translocation into different organelles where it elicits distinctly different functions than its best known activity as a plasma membrane-bound receptor tyrosine kinase. EGFR can be shuttled into the cell nucleus and mitochondrion upon ligand binding, radiation, EGFR-targeted therapy and other stimuli. Nuclear EGFR behaves as transcriptional regulator, tyrosine kinase, and mediator of other physiological processes. The role of mitochondrial EGFR remains poorly understood but it appears to regulate apoptosis and autophagy. While studies using patient tumors have shown nuclear EGFR to be an indicator for poor clinical outcomes in cancer patients, the impact of mitochondrial EGFR on tumor behavior and patient prognosis remains to be defined. Most recently, several lines of evidence suggest that mislocated EGFR may regulate tumor response to therapy and that plasma membrane-bound EGFR elicits survival signals independent of its kinase activity. In light of these recent progresses and discoveries, we will outline in this minireview an emerging line of research that uncovers and functionally characterizes several novel modes of EGFR signaling that take center stage in the cell nucleus, mitochondrion and other subcellular compartments. We will also discuss the clinical implications of these findings in the rationale design for therapeutic strategy that overcomes tumor drug resistance.Landscape of EGFR signaling network in human cancers: Biology and therapeutic response in relation to receptor subcellular locations - Corrected ProofWoody Han, Hui-Wen Lo10.1016/j.canlet.2012.01.011Cancer Letters (2012)2012-02-03Cancer Letters2012-02-03MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512000432/abstract?rss=yesAbstract: Sorafenib is a multi-kinase inhibitor applicable to hepatocellular carcinoma (HCC), but its limited therapeutic effects are a major problem to be solved. Here, we show that blockade of ataxia telangiectasia mutated (ATM) improves the antitumor effects of sorafenib. When hepatoma cell lines HepG2 and PLC/PRF/5 were treated with sorafenib plus ATM small inhibitory RNAs, ATM inhibitor KU55933 or caffeine, Akt signaling was suppressed and the cytotoxic effects were significantly potentiated. Moreover, ATM inhibition effectively suppressed the sorafenib-induced cell migration. Taken together, manipulation of ATM activity might be a useful strategy for improving sorafenib treatment of HCC.Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling - Corrected ProofShun Fujimaki, Yasunobu Matsuda, Toshifumi Wakai, Ayumi Sanpei, Masayuki Kubota, Masaaki Takamura, Satoshi Yamagiwa, Masahiko Yano, Shogo Ohkoshi, Yutaka Aoyagi10.1016/j.canlet.2011.12.043Cancer Letters (2012)2012-02-03Cancer Letters2012-02-03http://www.cancerletters.info/article/PIIS0304383512000298/abstract?rss=yesAbstract: The knockdown of Pim-1 or inhibition of Pim-1 activity significantly increased γ-H2A.X expression. The effect was correlated to apoptosis and was attributed to the inhibition of nonhomologous DNA-end-joining (NHEJ) repair activity supported by the following observations: (1) inhibition of ATM and DNA-PKcs activities, (2) down-regulation of Ku expression and nuclear localization and (3) decrease of DNA end-binding of both Ku70 and Ku80. The data suggest that Pim-1 plays a crucial role in the regulation of NHEJ repair. In the absence of Pim-1, the ability of DNA repair significantly decreases when exposed to paclitaxel, leading to severe DNA damage and apoptosis.Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair - Corrected ProofJui-Ling Hsu, Pui-Kei Leong, Yunn-Fang Ho, Lih-Ching Hsu, Pin-Hsuan Lu, Ching-Shih Chen, Jih-Hwa Guh10.1016/j.canlet.2012.01.004Cancer Letters (2012)2012-02-02Cancer Letters2012-02-02http://www.cancerletters.info/article/PIIS0304383512000304/abstract?rss=yesAbstract: The mammalian target of rapamycin (mTOR) plays a key role in regulation of cellular metabolism, growth, and proliferation. The frequent hyperactivation of mTOR signaling makes it an attractive target for therapeutic intervention and has driven the development of a number of mTOR inhibitors. Encouraging data from preclinical studies have resulted in initiation of multiple clinical trials. Furthermore, combinational strategies are being studied in an effort to overcome resistance and enhance efficacy. Although additional studies are required to determine their specific role in the clinical setting, mTOR inhibitors remain a promising therapeutic option for the treatment of cancer.mTOR inhibitors in cancer therapy - Corrected ProofYekaterina Y. Zaytseva, Joseph D. Valentino, Pat Gulhati, B. Mark Evers10.1016/j.canlet.2012.01.005Cancer Letters (2012)2012-02-02Cancer Letters2012-02-02MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512000341/abstract?rss=yesAbstract: Reactive oxygen species (ROS) are usually involved in two opposite procedures related to cancer: initiation, progression and metastasis of cancer, as well as in all non-surgical therapeutic approaches for cancer, including chemotherapy, radiotherapy and photodynamic therapy. This review is concentrated in new therapeutic strategies that take advantage of increased ROS in cancer cells to enhance therapeutic activity and selectivity. Novel biophotonic techniques for manipulation and characterization of drug delivery nanosystems in cancer therapy are discussed, including optical tweezers and atomic force microscopy. This review highlights how these techniques are playing a critical role in recent and future cancer fighting applications. We can conclude that Biophotonics and nanomedicine are the future for cancer biology and disease management, possessing unique potential for early detection, accurate diagnosis, dosimetry and personalized treatment of biomedical applications targeting cancer.Biophotonic techniques for manipulation and characterization of drug delivery nanosystems in cancer therapy - Corrected ProofE. Spyratou, M. Makropoulou, E.A. Mourelatou, C. Demetzos10.1016/j.canlet.2011.12.039Cancer Letters (2012)2012-02-02Cancer Letters2012-02-02MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512000353/abstract?rss=yesAbstract: Aquaporin 3 (AQP3) and c-Met are both overexpressed in human gastric carcinoma and highly associated with its metastasis and invasion. However, it still remains unknown whether c-Met and AQP3 correlate with each other. Herein, we demonstrated that c-Met expression in gastric cancer tissues significantly correlated with differentiation, lymph node metastasis and lymphovascular invasion, and c-Met exhibited marked association with AQP3 expression. Immunoblotting assays showed that hHGF phosphorylated c-Met in SGC7901 and AGS cells and upregulated AQP3 expression in a dose- or time-dependent way. RNAi against c-Met reduced total c-Met levels by about two thirds in both AGS and SGC7901 cells and attenuated hHGF-induced AQP3 expression significantly. In vitro migration and proliferation assays showed that siRNA against AQP3 noticeably restrained HGF-promoted migration and proliferation of these cells. Furthermore, Immunoblotting studies revealed that HGF induced phosphorylation of ERK, and pre-treatment with U0126, a MAPK/ERK inhibitor, partially inhibited hHGF-induced increase in AQP3 expression. Together, these data provide initial evidence that c-Met regulates the expression of AQP3 via the ERK signalling pathway in gastric carcinoma. These findings assist in understanding the mechanism of growth and invasion of gastric carcinoma, and provide a possible strategy for the inhibition of gastric tumor metastasis.c-Met upregulates aquaporin 3 expression in human gastric carcinoma cells via the ERK signalling pathway - Corrected ProofJianping Wang, Zhifu Gui, Longying Deng, Maocai Sun, Renhua Guo, Weiming Zhang, Lizong Shen10.1016/j.canlet.2011.12.040Cancer Letters (2012)2012-02-02Cancer Letters2012-02-02http://www.cancerletters.info/article/PIIS0304383512000407/abstract?rss=yesAbstract: All-trans retinoic acid (ATRA) is a promising therapeutic agent, but exhibits low efficacy against human cancers. We investigated the effect of sphingosine-1-phosphate (S1P) on ATRA activity in human colon cancer HT-29 cells. S1P antagonized ATRA activity on HT-29 cell proliferation and retinoic acid receptor beta (RARβ) expression. S1P treatment or transient co-transfection with SphK2 expression vector antagonized ATRA-induced RARβ promoter activity. Proteasome inhibition prevented S1P-induced modulation of ATRA activity. Overall, S1P antagonized ATRA’s inhibitory effects by down-regulating RARβ expression, likely via the proteasome-dependent pathway. Decreasing S1P production or inhibiting SphK2 activity could enhance the efficacy of retinoids in cancer treatments.Sphingosine 1-phosphate antagonizes the effect of all-trans retinoic acid (ATRA) in a human colon cancer cell line by modulation of RARβ expression - Corrected ProofDe-Fu Sun, Zu-Hua Gao, Hui-Ping Liu, Yi Yuan, Xian-Jun Qu10.1016/j.canlet.2012.01.012Cancer Letters (2012)2012-02-02Cancer Letters2012-02-02http://www.cancerletters.info/article/PIIS0304383512000420/abstract?rss=yesAbstract: Ras gene is frequently mutated, and also associated with increased Ras expression and its GTPase activity (activity) in pancreatic cancer (PC), which could in part be due to deregulated expression of microRNAs (miRNAs) contributing to tumor aggressiveness. Here we report, for the first time, that Ras expression and its activity were significantly higher in MIAPaCa-2 cells compared to COLO-357 and BxPC-3 cell lines, which was correlated with loss of let-7 family and miR-143 expression in MIAPaCa-2 cells compared to COLO-357 and BxPC-3 cells. Whereas the expression of miR-21, a frequently up-regulated miRNA in solid tumors was up-regulated in MIAPaCa-2 cells and it was correlated with increased Ras expression and its activity. The miRNAs, let-7i and miR-143 was found to target Ras, and forced re-expression of let-7i and miR-143 inhibited Ras activity, cell proliferation and colony formation in vitro. We also found that the treatment of cells in vitro or treatment of MIAPaCa-2 induced tumors in vivo with CDF, a novel synthetic analog of curcumin, led to the re-expression of let-7 and miR-143, and down-regulated miR-21 expression, which was consistent with attenuation of Ras expression and its activity. Moreover, re-expression of let-7i in vivo resulted in decreased tumor growth and Ras activity. These results suggest that the loss of expression of let-7 and miR-143, and increased expression of miR-21 leads to increased expression of Ras and its GTPase activity, which could be attenuated by CDF treatment and, thus CDF could become a novel therapeutic agent for the treatment of PC.Increased Ras GTPase activity is regulated by miRNAs that can be attenuated by CDF treatment in pancreatic cancer cells - Corrected ProofShadan Ali, Aamir Ahmad, Amro Aboukameel, Bin Bao, Subhash Padhye, Philip A. Philip, Fazlul H. Sarkar10.1016/j.canlet.2012.01.013Cancer Letters (2012)2012-02-02Cancer Letters2012-02-02http://www.cancerletters.info/article/PIIS0304383512000249/abstract?rss=yesAbstract: Hormone secretion, metabolism, and the cell cycle are under rhythmic control. Lack of rhythmic control has been predicted to lead to uncontrolled proliferation and cancer. Consistent with this prediction are findings that circadian disruption by dim light at night or chronic jet lag accelerates tumor growth in desynchronized animals. Circadian controlled factors such as insulin/IGF-1, glucocorticoids, catecholamines, and melatonin have be implicated in controlling tumor growth in the desynchronized animals. Recent attention has focused on the signaling pathways activated by the circadian controlled factors because these pathways hold the potential for the development of novel strategies for cancer prevention and treatment.Circadian rhythms and tumor growth - Corrected ProofMichael W. Greene10.1016/j.canlet.2012.01.001Cancer Letters (2012)2012-02-01Cancer Letters2012-02-01MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383511007713/abstract?rss=yesAbstract: Apoptosis is a conserved and regulated cell suicide process, the malfunction of which is closely linked with carcinogenesis. Caspases control the induction of apoptosis through an enzymatic cascade that can be activated by both the mitochondrial and death receptor pathways. Smac is a mitochondrial protein that interacts with Inhibitor of Apoptosis Proteins (IAPs) and, upon apoptotic stimuli, is released into the cytoplasm to inhibit the capase-binding activity of IAPs. Smac plays key roles in both the diagnosis and treatment of cancer, especially lung cancer. Our review will focus on the roles of Smac in lung carcinogenesis and cancer progression and its relevance in lung cancer treatment.Smac: Its role in apoptosis induction and use in lung cancer diagnosis and treatment - Corrected ProofSida Qin, Chengcheng Yang, Shuo Li, Chongwen Xu, Yang Zhao, Hong Ren10.1016/j.canlet.2011.12.024Cancer Letters (2012)2012-01-30Cancer Letters2012-01-30MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512000110/abstract?rss=yesAbstract: Ovarian cancer is the most lethal gynecological malignancy and the 5th leading cause of cancer death in women. Women with ovarian cancer are typically diagnosed at late stage, when the cancer has spread into the peritoneal cavity and complete surgical removal is difficult. The 5-year survival time for patients diagnosed at this stage is 30%, in contrast to a 5-year survival of 90% for patients diagnosed at early stage. Cancer screening and early detection have the potential to greatly decrease the mortality and morbidity from cancer. The emerging field of epigenetics offers a valuable opportunity to identify cancer-specific DNA methylation changes that can be used in the clinic to improve early-stage diagnosis and better predict response in treated patients.To date, numerous DNA methylation aberrations have been identified in epithelial ovarian cancer; here we review some candidate genes and pathways with potential clinical utility as biomarkers for diagnosis and/or prognosis. It has become clear that even with the great promise of DNA methylation biomarkers in epithelial ovarian cancer, the identification of highly specific, sensitive and robust panels of markers and the standardization of analysis techniques are still required in order to improve detection, treatment and thus patient outcome.Epigenetic biomarkers in epithelial ovarian cancer - Corrected ProofBrian S. Gloss, Goli Samimi10.1016/j.canlet.2011.12.036Cancer Letters (2012)2012-01-30Cancer Letters2012-01-30MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383511006550/abstract?rss=yesAbstract: Herein we present a novel molecular mechanism of the antitumor effects of live-attenuated measles virus (MV) vaccine in ovarian cancer. Using a 2-DE/MS-based comparative proteomics strategy, we identified 17 proteins differentially expressed in live-attenuated MV vaccine-treated SKOV-3 ovarian cancer cells, including oxidative stress-associated enzymes and cell contact-related proteins, which indicated that live-attenuated MV vaccine could induce aberrant ROS activation. It further mediated epigenetic silencing of E-cadherin via upregulating DNMT3a that conferred both cell–cell and cell–matrix contact loss and apoptosis of ovarian cancer cells. This process could be reversed through ROS inhibition. Our study lays the theoretical foundation for the clinical application of live-attenuated MV vaccine as a potential oncotherapeutic agent for ovarian cancer treatment.Live-attenuated measles virus vaccine confers cell contact loss and apoptosis of ovarian cancer cells via ROS-induced silencing of E-cadherin by methylation - Corrected ProofShengtao Zhou, Yuhua Li, Fuqiang Huang, Boya Zhang, Tao Yi, Zhengyu Li, Hong Luo, Xiang He, Qian Zhong, Ce Bian, Xiaojuan Lin, Xiaorong Qi, Ping Liu, Canhua Huang, Xia Zhao, Yuquan Wei10.1016/j.canlet.2011.10.038Cancer Letters (2012)2012-01-24Cancer Letters2012-01-24http://www.cancerletters.info/article/PIIS0304383511007683/abstract?rss=yesAbstract: Apoptosis is a form of programmed cell death that is controlled at the mitochondrion by the BCL-2 family of proteins. While much has been learned about the structure and function of these proteins over the past two decades, the important goal of predicting cell fate decisions in response to toxic stimuli is largely unrealized. BH3 profiling is a functional approach that can be used to predict cellular responses to stimuli based on measuring the response of mitochondria to perturbation by a panel of BH3 domain peptides. BH3 profiling has proven useful in identifying and understanding cellular dependence on individual anti-apoptotic proteins like BCL-2 or MCL-1. Consequently, it can also be used to predict cellular response to chemotherapy agents such as ABT-737 that target these individual proteins.BH3 profiling – Measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions - Corrected ProofVictoria Del Gaizo Moore, Anthony Letai10.1016/j.canlet.2011.12.021Cancer Letters (2012)2012-01-24Cancer Letters2012-01-24MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383511007907/abstract?rss=yesAbstract: Circulating tumor cells (CTCs) can be enumerated using CellSearch, but not all breast cancer subtypes, specifically those with epithelial-mesenchymal transition (EMT) characteristics, sufficiently express the enrichment (EpCAM) and selection (CK8/18/19) markers used in this method. While CD146 can detect EpCAM-negative CTCs, we here evaluated the value of various cytokeratins and CD49f to detect CK8/18/19-negative CTCs. The tested cytokeratins provided no substantial benefit, but adding CD49f to CK8/18/19 as a selection marker resulted in improved recovery of normal-like cell lines.Combined staining of CK8/18/19 and CD49f after CD146/EpCAM enrichment is likely to further improve CTC detection in breast cancer.CD49f-based selection of circulating tumor cells (CTCs) improves detection across breast cancer subtypes - Corrected ProofBianca Mostert, Jaco Kraan, Anieta M. Sieuwerts, Petra van der Spoel, Joan Bolt-de Vries, Wendy J.C. Prager-van der Smissen, Marcel Smid, Annemieke M. Timmermans, John W.M. Martens, Jan W. Gratama, John A. Foekens, Stefan Sleijfer10.1016/j.canlet.2011.12.031Cancer Letters (2012)2012-01-24Cancer Letters2012-01-24http://www.cancerletters.info/article/PIIS0304383511007920/abstract?rss=yesAbstract: Obesity is generally acknowledged as a risk factor for endometrial cancer, as accumulated adipocytes partly contribute to the increased production of estrogen which is involved in dysregulated cell growth and metastasis in early endometrial carcinogenesis. Thus we evaluated in this study expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored its role in β-estradiol (E2)-induced endometrial cancer cell proliferation and invasion. IHC staining showed that FTO overexpressed in endometrial carcinoma. Additionally, E2-induced FTO via activation of the PI3K/AKT and MPAK signal pathways contributed to enhanced proliferation and invasion. Therefore, this study provides a new insight on the mechanisms of E2-induced proliferation and invasion and the link between obesity and endometrial cancer, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer.Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways - Corrected ProofZhenbo Zhang, Dongmei Zhou, Yunli Lai, Yongjuan Liu, Xiang Tao, Qianqian Wang, Guixu Zhao, Hongqin Gu, Hong Liao, Yaping Zhu, Xiaowei Xi, Youji Feng10.1016/j.canlet.2011.12.033Cancer Letters (2012)2012-01-24Cancer Letters2012-01-24http://www.cancerletters.info/article/PIIS0304383511007932/abstract?rss=yesAbstract: Pyrvinium pamoate (PP), a classical anthelminthic, potently inhibited proliferation and STAT3 Tyr705 phosphorylation of human myeloma (U266B1 and PCM6)/erythroleukemia (HEL 92.1.7) cells. PCM6 cell proliferation was markedly impaired by STAT3 siRNA knockdown. PP inhibited ATP production/O2 consumption in those three cells and mitochondrial respiratory complex (I+III, but not II+III) activity in mouse kidney mitochondrial fractions. PP inhibition of ATP production, STAT3 Tyr705 phosphorylation, and proliferation was absent in mitochondrial DNA-deficient HEL 92.1.7-ρ0 cells. Moreover, PP acted synergistically with dexamethasone to inhibit PCM6 cell proliferation. In conclusion, we identified PP as a potential anticancer drug directed against mitochondrial respiratory complex I/STAT3.Pyrvinium pamoate inhibits proliferation of myeloma/erythroleukemia cells by suppressing mitochondrial respiratory complex I and STAT3 - Corrected ProofYasuo Harada, Isao Ishii, Kiyohiko Hatake, Tadashi Kasahara10.1016/j.canlet.2011.12.034Cancer Letters (2012)2012-01-24Cancer Letters2012-01-24http://www.cancerletters.info/article/PIIS0304383511007440/abstract?rss=yesAbstract: The transient receptor potential TRPM7 ion channel is required for cellular proliferation in pancreatic epithelia and adenocarcinoma. To elucidate the mechanism that mediates the function of TRPM7, we examined its role in survival of pancreatic cancer cells. RNA interference-mediated silencing of TRPM7 did not induce apoptotic cell death. TRPM7-deficient cells underwent replicative senescence with up-regulation of p16CDKN2A and WRN mRNA. The combination of anti-TRPM7 siRNA and gemcitabine produced enhanced cytotoxicity as compared to gemcitabine alone. Thus, TRPM7 is required for preventing senescence, and modulation of TRPM7 expression may help improve treatment response of pancreatic cancer by combining with apoptosis-inducing agents.Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma - Corrected ProofNelson S. Yee, Weiqiang Zhou, Minsun Lee, Rosemary K. Yee10.1016/j.canlet.2011.12.007Cancer Letters (2012)2012-01-16Cancer Letters2012-01-16http://www.cancerletters.info/article/PIIS0304383511007737/abstract?rss=yesAbstract: Prostate, bladder, kidney and testis cancers, the most common genitourinary (GU) neoplasms, are generally clinically silent at their earliest stages when curative treatment is most likely successful. However, there are no consensual guidelines for GU cancer screening and available methods are characterized by suboptimal sensitivity and specificity. Moreover, standard clinical and pathological parameters meet with important limitations in the assessment of prognosis in an individual basis. Herein, we focus on the development of epigenetic-based GU cancer biomarkers, which have emerged from exploratory studies in recent years and that hold the promise to revolutionize the clinical management of GU cancer patients.Epigenetic biomarkers in urological tumors: A systematic review - Corrected ProofCarmen Jerónimo, Rui Henrique10.1016/j.canlet.2011.12.026Cancer Letters (2012)2012-01-16Cancer Letters2012-01-16MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383511005271/abstract?rss=yesHighlights: ► We describe the characteristics of MSCs from MDS patients (MDS–MSCs) at single cell level. ► MDS–MSCs were similar to normal-MSCs in growth property and differentiation ability. ► MDS–MSCs had normal karyotype and may be nonmalignant. ► MDS–MSCs appear to be impaired immunomodulatory and hematopoiesis support functions. ► The impaired MDS–MSCs might play a critical role in the pathogenesis of MDS.Abstract: Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of immunomodulatory and supporting hematopoiesis. Nevertheless, it is unclear whether the characteristics of MSCs are altered in diseased states. In this study, we obtained and expanded MSCs from bone marrow of patients with myelodysplastic syndromes (MDS). Our results showed that MSCs derived from MDS (MDS–MSCs) were similar to normal adult bone marrow derived MSCs in morphology, growth property, surface epitopes, and differentiation ability in vitro. In addition, MDS–MSCs had normal karyotype and ultrastructure. However, MDS–MSCs appeared to be impaired in immunomodulatory and supporting hematopoiesis function. Although, MDS–MSCs could express hematopoietic cytokines and support hematopoiesis in long term culture, Real time quantitative polymerase chain reaction showed that the expression of hematopoietic cytokines in MDS–MSCs was much lower than that of normal adult derived MSCs. Moreover, MDS–MSCs showed reduced hematopoiesis support function, as compared to their normal counterparts. Lastly, the capacity of MDS–MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. These results indicate that MDS–MSCs have impaired immunomodulatory and hematopoiesis support functions, suggesting their critical role in the pathogenesis of MDS.Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes - Corrected ProofZhi-Gang Zhao, Wen Xu, Hai-Peng Yu, Bing-Ling Fang, Shu-Hong Wu, Fang Li, Wei-Min Li, Qiu-Bai Li, Zhi-Chao Chen, Ping Zou10.1016/j.canlet.2011.08.030Cancer Letters (2012)2012-01-13Cancer Letters2012-01-13http://www.cancerletters.info/article/PIIS0304383511007580/abstract?rss=yesAbstract: Bone loss/resorption or osteoporosis is a disease that is accelerated with aging and age-associated chronic diseases such as cancer. Bone loss has been associated with human multiple myeloma, breast cancer, and prostate cancer and is usually treated with a bisphosphonate. Because of the numerous side effects of the currently available drugs, the search continues for safe and effective therapies for bone loss. Recently, receptor activator of NF-κB ligand (RANKL), a member of the TNF superfamily, has emerged as a major mediator of bone loss via activation of osteoclastogenesis. We have identified cardamonin, a chalcone first isolated from grass cardamom (Alpinia katsumadai Hayata), that can affect osteoclastogenesis through modulation of RANKL. We found that treatment of monocytes with cardamonin suppressed RANKL-induced NF-κB activation and this suppression correlated with inhibition of IκBα kinase and of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. Cardamonin suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. We also found that an NF-κB-specific inhibitory peptide blocked RANKL-induced osteoclastogenesis, indicating a direct link with NF-κB. Finally, osteoclastogenesis induced by human breast cancer cells or human multiple myeloma cells was completely suppressed by cardamonin. Collectively, our results indicate that cardamonin suppresses osteoclastogenesis induced by RANKL and tumor cells by suppressing activation of the NF-κB pathway.Cardamonin inhibits osteoclastogenesis induced by tumor cells through interruption of the signaling pathway activated by receptor activator of NF-κB ligand - Corrected ProofVivek R. Yadav, Sahdeo Prasad, Simone Reuter, Bokyung Sung, Norio Yamamoto, Akira Murakami, Bharat B. Aggarwal10.1016/j.canlet.2011.12.011Cancer Letters (2012)2012-01-13Cancer Letters2012-01-13http://www.cancerletters.info/article/PIIS0304383511007725/abstract?rss=yesAbstract: Formation of γ-H2AX in response to DNA double stranded breaks (DSBs) provides the basis for a sensitive assay of DNA damage in human biopsies. The review focuses on the application of γ-H2AX-based methods to translational studies to monitor the clinical response to DNA targeted therapies such as some forms of chemotherapy, external beam radiotherapy, radionuclide therapy or combinations thereof. The escalating attention on radiation biodosimetry has also highlighted the potential of the assay including renewed efforts to assess the radiosensitivity of prospective radiotherapy patients. Finally the γ-H2AX response has been suggested as a basis for an in vivo imaging modality.Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research - Corrected ProofAlesia Ivashkevich, Christophe E. Redon, Asako J. Nakamura, Roger F. Martin, Olga A. Martin10.1016/j.canlet.2011.12.025Cancer Letters (2012)2012-01-13Cancer Letters2012-01-13MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383511007944/abstract?rss=yesAbstract: The adhesion molecule L1CAM (CD171) accounts for enhanced motility, invasiveness and chemoresistance of tumor cells and represents a novel marker for various tumor entities including pancreatic and ovarian carcinoma. Recently, we showed that L1CAM inhibition increases the apoptotic response of tumor cells towards cytostatic drugs pointing to the potential of L1CAM to serve as a chemosensitizer in anti-cancer therapy. Thus, the present study evaluated the therapeutic potential of combined treatment with L1CAM antibodies and chemotherapeutic drugs in pancreatic and ovarian carcinoma model systems in vivo. Two L1CAM-specific antibodies (L1-14.10 and L1-9.3/2a) exhibiting high binding affinity to the L1CAM expressing pancreatic adenocarcinoma cell line Colo357 and the ovarian carcinoma cell line SKOV3ip were used for treatment. The combined therapy of SCID mice with either L1CAM antibody and gemcitabine and paclitaxel, respectively, reduced the growth of subcutaneously grown Colo357 or SKOV3ip tumors more efficiently than treatment with the cytostatic drug alone or in combination with control IgG. This was accompanied by an increased number of apoptotic tumor cells along with an elevated procaspase-8 expression. Furthermore, a lowered activation of NF-κB along with a reduced expression of VEGF and a diminished number of CD31-positive blood vessels were observed in tumors after combined therapy compared to control treatments, while the infiltration of F4/80-positive macrophages increased. Overall, these data provide new insights into the mechanism of the anti-cancer activity of L1CAM-blocking antibodies in vivo and support the suitability of L1CAM as a target for chemosensitization and of L1CAM-interfering antibodies as an appropriate tool to increase the therapeutic response of pancreatic and ovarian carcinoma.Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma - Corrected ProofHeiner Schäfer, Chantal Dieckmann, Olena Korniienko, Gerhard Moldenhauer, Helena Kiefel, Alexey Salnikov, Achim Krüger, Peter Altevogt, Susanne Sebens10.1016/j.canlet.2011.12.035Cancer Letters (2012)2012-01-13Cancer Letters2012-01-13http://www.cancerletters.info/article/PIIS0304383511007592/abstract?rss=yesAbstract: Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes.Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury - Corrected ProofEdouard I. Azzam, Jean-Paul Jay-Gerin, Debkumar Pain10.1016/j.canlet.2011.12.012Cancer Letters (2012)2012-01-11Cancer Letters2012-01-11MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383511007646/abstract?rss=yesAbstract: Leukemic stem cells (LSCs) play the central role in the relapse and refractory of acute myeloid leukemia (AML) and highlight the critical need for the new therapeutic strategies to directly target the LSC population. However, relatively little is known about the unique molecular mechanisms of drug and natural killer cells (NK)-killing resistance of LSCs because of very small number of LSCs in bone marrow. In this study, we investigated whether established leukemia cell line contains LSCs. We showed that KG1a leukemia cell line contained leukemic stem-like cells, which have been phenotypically restricted within the CD34+CD38− fractions. CD34+CD38− cells could generate CD34+CD38+ cells in culture medium and had renewal function. Moreover, CD34+CD38− cells had self-renewal potential. We found that leukemic stem-like cells from KG1a cells were resistant to chemotherapy and NK-mediated cytotoxicity. NKG2D ligands involve in protecting LSCs from NK-mediated attack. Taken together, our studies provide a novel cell model for leukemic stem cells research. Our data also shed light on mechanism of double resistant to chemotherapy and NK cell immunotherapy, which was helpful for developing novel effective strategies for LSCs.Resistance of leukemic stem-like cells in AML cell line KG1a to natural killer cell-mediated cytotoxicity - Corrected ProofMiaorong She, Xinqing Niu, Xilin Chen, Jinggao Li, Maohua Zhou, Yanjie He, Yi Le, Kunyuan Guo10.1016/j.canlet.2011.12.017Cancer Letters (2012)2012-01-09Cancer Letters2012-01-09http://www.cancerletters.info/article/PIIS0304383511007671/abstract?rss=yesAbstract: Defects in natural killer (NK) cell function are necessary for tumor immune escape, but the underlying regulatory mechanisms in human cancers remain largely unknown. Here we show that fibroblasts derived from hepatocellular carcinoma (HCC) were significantly superior to foreskin-derived fibroblasts at inducing NK cell dysfunction, which is characterized by low expression of cytotoxic molecules and surface markers for cell activation, impaired production of cytokines, and decreased cytotoxicity against K562 cells in vitro. Our results also indicate that PGE2 and IDO, derived from activated fibroblasts, suppress the activation of NK cells and thereby create favorable conditions for tumor progression.Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO - Corrected ProofTuanjie Li, Yang Yang, Xuefeng Hua, Guoying Wang, Wei Liu, Changchang Jia, Yan Tai, Qi Zhang, Guihua Chen10.1016/j.canlet.2011.12.020Cancer Letters (2012)2012-01-09Cancer Letters2012-01-09http://www.cancerletters.info/article/PIIS0304383511007695/abstract?rss=yesAbstract: The aromatic amine 4-aminobiphenyl (ABP) is a liver procarcinogen in mice, requiring enzymatic bioactivation to exert its tumorigenic effect. To assess the role of arylamine N-acetyltransferase (NAT)-dependent acetylation capacity in the risk for ABP-induced liver tumors, we compared 1-year liver tumor incidence following the postnatal exposure of wild-type and NAT-deficient Nat1/2(−/−) mice to ABP. At an ABP exposure of 1200nmol, male Nat1/2(−/−) mice had a liver tumor incidence of 36% compared to 69% in wild-type males, and at 600nmol there was a complete absence of tumors compared to 60% in wild-type mice. Only one female wild-type mouse had a tumor using this exposure protocol. However, levels of N-deoxyguanosin-8-yl-ABP-DNA adducts did not correlate with either the strain or sex differences in tumor incidence. These results suggest that female sex and NAT deficiency reduce risk for ABP-induced liver tumors, but by mechanisms unrelated to differences in DNA-damaging events.Reduced 4-aminobiphenyl-induced liver tumorigenicity but not DNA damage in arylamine N-acetyltransferase null mice - Corrected ProofKim S. Sugamori, Debbie Brenneman, Otto Sanchez, Mark A. Doll, David W. Hein, William M. Pierce, Denis M. Grant10.1016/j.canlet.2011.12.022Cancer Letters (2012)2012-01-09Cancer Letters2012-01-09http://www.cancerletters.info/article/PIIS0304383511007749/abstract?rss=yesAbstract: We have shown that the ectopic expression of Interferon Regulatory Factor 1 (IRF-1) results in human cancer cell death accompanied by the down-regulation of the Inhibitor of Apoptosis Protein (IAP) survivin and the induction of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. In this report, we investigated the direct role of p21 in the suppression of survivin. We show that IRF-1 down-regulates cyclin B1, cdc-2, cyclin E, E2F1, Cdk2, Cdk4, and results in p21-mediated G1 cell cycle arrest. Interestingly, while p21 directly mediates G1 cell cycle arrest, IRF-1 or other IRF-1 signaling pathways may directly regulate survivin in human cancer cells.Interferon Regulatory Factor 1 (IRF-1) induces p21WAF1/CIP1 dependent cell cycle arrest and p21WAF1/CIP1 independent modulation of survivin in cancer cells - Corrected ProofMichaele J. Armstrong, Michael T. Stang, Ye Liu, Jinbo Gao, Baoguo Ren, Brian S. Zuckerbraun, Raja S. Mahidhara, Quanhua Xing, Eva Pizzoferrato, John H. Yim10.1016/j.canlet.2011.12.027Cancer Letters (2012)2012-01-09Cancer Letters2012-01-09http://www.cancerletters.info/article/PIIS0304383511007750/abstract?rss=yesAbstract: The present study further investigated the mode of action of methyl jasmonate (MJ) in different cervical cancer cell lines. We show that in addition to the short term cytotoxicity, MJ effectively reduced the survival of cervical cancer cells (clonogenicity assays). MJ induced apoptosis in all cervical cancer cells. In some cell lines, MJ caused elevation of the mitochondrial superoxide anion, notably, in HeLa and CaSki. Changes in the expression of p53 and bax were variable, yet, downregulation of survivin was common to all cervical cancer cells. MJ significantly reduced the levels of the human papillomavirus (HPV) E6 and E7 proteins without alteration of the mRNA levels. Moreover, ectopic expression of E6, E7 or both in cervical cancer cells that lack HPV (C33A), did not alter significantly their response to MJ. Our studies point to MJ as an effective anticancer agent against a variety of cervical cancer cells acting through shared and different pathways to induce cell death regardless of the presence of HPV.Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin - Corrected ProofElad Milrot, Anna Jackman, Tatiana Kniazhanski, Pinhas Gonen, Eliezer Flescher, Levana Sherman10.1016/j.canlet.2011.12.028Cancer Letters (2012)2012-01-09Cancer Letters2012-01-09http://www.cancerletters.info/article/PIIS0304383511007890/abstract?rss=yesAbstract: The original theory of the multi-step process of colorectal cancer (CRC), suggesting that the disease resulted from the accumulation of mutations in oncogenes and tumor suppressor genes in colonic mucosa cells, has been largely revised following the observation that epigenetic modifications of several genes occur in the average CRC genome. Therefore, the current opinion is that CRCs are the consequence of the accumulation of both mutations and epigenetic modifications of several genes. This mini-review article focuses on DNA methylation biomarkers in CRC. Recent large-scale DNA methylation studies suggest that CRCs can be divided into at least three-four subtypes according to the frequency of DNA methylation and those of mutations in key CRC genes. Despite hundreds of genes might be epigenetically modified in CRC cells, there is interest in the identification of DNA methylation biomarkers to be used for CRC diagnosis, progression, tendency to tissue invasion and metastasis, prognosis, and response to chemotherapeutic agents. Moreover, DNA methylation largely depends on one-carbon metabolism, the metabolic pathway required for the production of S-adenosylmethionine, the major intracellular methylating agent. Complex interactions are emerging among dietary one-carbon nutrients (folates, vitamin B6, vitamin B12, methionine, and others), their metabolic genes, CRC risk, and DNA methylation profiles in CRC. Moreover, active research is also focused on the possible contribution of folic acid dietary fortification during pregnancy and the possible methylation of CRC-related genes in the offspring.Epigenetic biomarkers of colorectal cancer: Focus on DNA methylation - Corrected ProofFabio Coppedè10.1016/j.canlet.2011.12.030Cancer Letters (2012)2012-01-09Cancer Letters2012-01-09MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383511007919/abstract?rss=yesAbstract: We investigated the anticancer activity of erufosine in oral squamous carcinoma cell lines in terms of cell proliferation, colony formation, induction of autophagy/apoptosis, cell cycle and mTOR signaling pathway. Erufosine showed dose-dependent cytotoxicity in all cell lines, it induced autophagy as well as apoptosis, G2 cell cycle arrest and modulation of cyclin D1 expression. Further erufosine downregulated the phosphorylation of major components of mTOR pathway, like p-Akt at Ser473 and Thr308 residues, p-Raptor, p-mTOR, p-PRAS40 and its downstream substrates p-p70S6K and p-4EBP1 in a dose-dependent manner. The pre-treatment of tumor cells with p-mTOR siRNA increased cytotoxic effects of erufosine comparable to cisplatin but higher than rapamycin.Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt–mTOR signaling pathway in oral squamous cell carcinoma - Corrected ProofVaishali Kapoor, Maya M. Zaharieva, Satya N. Das, Martin R. Berger10.1016/j.canlet.2011.12.032Cancer Letters (2012)2012-01-09Cancer Letters2012-01-09http://www.cancerletters.info/article/PIIS0304383511007385/abstract?rss=yesAbstract: Neuroblastoma (NB) is the most common solid extracranial tumor in children. Here we showed that trichostatin A, a histone deacetylase inhibitor (HDACi), decreases cell viability in three NB cell lines of different phenotypes. The treatment leads to G2/M-phase arrest, apoptosis and autophagy. Autophagy induction accompanies apoptosis in the most proliferative, N-Myc overexpressing cells. In contrast, autophagy precedes apoptosis and acts as a protective mechanism in the less proliferative, non-N-Myc overexpressing cells. Therefore, the autophagy induction is a relevant event in the NB response to HDACis, and it should be considered in the design of new treatments for this malignancy.Histone deacetylase inhibition induces apoptosis and autophagy in human neuroblastoma cells - Corrected ProofRoser Francisco, Alba Pérez-Perarnau, Constanza Cortés, Joan Gil, Albert Tauler, Santiago Ambrosio10.1016/j.canlet.2011.11.036Cancer Letters (2012)2012-01-05Cancer Letters2012-01-05http://www.cancerletters.info/article/PIIS0304383511007610/abstract?rss=yesAbstract: Blockade of VEGF signaling using RNA interferences, a neutralizing antibody, an antagonizing soluble VEGF receptor, and a receptor tyrosine kinase inhibitor induced anti-tumor effects in human astrocytoma U251-MG and fibrosarcoma HT-1080 in vitro in a dose-dependent manner. Furthermore, blockade of VEGF-A using the doxycycline-inducible VEGF-A RNA interference system showed a significant anti-tumor effect in a murine HT-1080-xenograft model. Anti-tumor effect through the blockade of VEGF signaling was mediated by FAK and AKT pathway in vitro and in vivo. These results collectively indicate that VEGF-A and its receptors can act as key inducer of tumor growth as well as angiogenesis.Blockade of VEGF-A suppresses tumor growth via inhibition of autocrine signaling through FAK and AKT - Corrected ProofJungwhoi Lee, Taeyun Ku, Hana Yu, Kyuha Chong, Seung-Wook Ryu, Kyungsun Choi, Chulhee Choi10.1016/j.canlet.2011.12.014Cancer Letters (2012)2012-01-05Cancer Letters2012-01-05http://www.cancerletters.info/article/PIIS0304383511007622/abstract?rss=yesAbstract: SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-2112 in A-375 cells. SNX-2112 induced the degradation of multiple Hsp90 client proteins, activated both the mitochondrial-mediated and death receptor-mediated apoptotic pathways, downregulated Bcl-2 and Bcl-xL, upregulated Bid, cleaved caspase-9, caspase-7, caspase-3 and PARP, and activated caspase-8. The general caspase inhibitor, z-VAD-fmk, did not completely abolish SNX-2112-induced cell death. SNX-2112 induced autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and autophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent.SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells - Corrected ProofKai-Sheng Liu, Hui Liu, Jin-Huan Qi, Qiu-Yun Liu, Zhong Liu, Min Xia, Guo-Wen Xing, Shao-Xiang Wang, Yi-Fei Wang10.1016/j.canlet.2011.12.015Cancer Letters (2012)2012-01-05Cancer Letters2012-01-05http://www.cancerletters.info/article/PIIS0304383511007634/abstract?rss=yesAbstract: The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A synergistic effect was observed when cells were coincubated with both drugs or preincubated with gemcitabine first. These administration sequences resulted in NASS cells in decreased ERCC1 and XPA expression, two key proteins of the NER DNA repair system, and increased platinum adduct formation in DNA. Most of these phenomena were not observed in SJNB8 cells which might explain the lack of synergy between cisplatin and gemcitabine in SJNB8 cells. Our results showed favorable interactions between cisplatin and gemcitabine in 4 out of 5 cell lines. Therefore, we feel that inclusion of gemcitabine into cisplatin-containing regiments might be a promising new strategy for the treatment of neuroblastoma.Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids - Corrected ProofOdette G. Besançon, Godelieve A.M. Tytgat, Rutger Meinsma, René Leen, Jerry Hoebink, Ganna V. Kalayda, Ulrich Jaehde, Huib N. Caron, André B.P. van Kuilenburg10.1016/j.canlet.2011.12.016Cancer Letters (2012)2012-01-05Cancer Letters2012-01-05http://www.cancerletters.info/article/PIIS0304383511007658/abstract?rss=yesAbstract: Dysregulation of E-cadherin and β-catenin function in cell–cell adhesion is common in nasopharyngeal carcinoma (NPC) and correlates with metastatic disease. In this study, we examined the role of EGF-activated phosphatidylinositol 3-kinase (PI3K)-Akt signaling in E-cadherin and β-catenin regulation. We found that reduced membranous E-cadherin and β-catenin expression was positively correlated with Akt phosphorylation in NPC tissues. EGF treatment disrupted cell–cell adhesion and resulted in mesenchymal morphological features in NPC cell lines (TW01, TW04, and TW06). Western blot analysis showed that the E-cadherin protein level was partially reduced in TW04 cells only and the β-catenin levels were not considerably affected upon EGF treatment. In contrast, quantitative real-time RT-PCR showed that the E-cadherin, but not β-catenin, mRNA levels were markedly reduced by EGF in all cell lines. Immunofluorescent staining revealed that E-cadherin and β-catenin appeared to be markedly reduced on the cell surface and more localized in the cytoplasm. Inhibition of PI3K by LY294002 did not abolish the EGF-induced downregulation of E-cadherin protein or mRNA in TW04 cells but moderately increased the β-catenin protein level in TW01 cells and mRNA level in TW06 cells. However, LY294002 substantially restored or increased cell surface E-cadherin and β-catenin in all EGF-treated cell lines, in concordance with the inhibition of cell morphological changes. Moreover, LY294002 significantly blocked EGF-driven cell invasion, correlating with the elevation of membranous E-cadherin and β-catenin levels. In conclusion, EGF-induced epithelial-to-mesenchymal transition may not be only dependent on downregulation of E-cadherin protein/mRNA but also on mislocalization of E-cadherin and β-catenin. The mechanisms involved may be related, at least in part, to the PI3K-Akt pathway.Activation of phosphatidylinositol 3-kinase/Akt signaling by EGF downregulates membranous E-cadherin and β-catenin and enhances invasion in nasopharyngeal carcinoma cells - Corrected ProofWai Kien Yip, Heng Fong Seow10.1016/j.canlet.2011.12.018Cancer Letters (2012)2012-01-05Cancer Letters2012-01-05http://www.cancerletters.info/article/PIIS0304383511007245/abstract?rss=yesAbstract: We and others have shown central roles of the Na+/H+ exchanger NHE1 in cell motility. The aim of this study was to determine the roles of NHE1 and of the Na+, cotransporter NBCn1 in motility of serum-starved MCF-7 breast cancer cells expressing constitutively active ErbB2 (ΔNErbB2). ΔNErbB2 expression elicited NBCn1 upregulation, Ser703-phosphorylation of NHE1, and NHE1-inhibitor (EIPA)-sensitive pericellular acidification, in conjunction with increased expression of β1 integrin and ERM proteins. Active ERM proteins and NHE1 colocalized strongly to invadopodial rosettes, the diameter of which was increased by ΔNErbB2. Adhesion and migration on collagen-I were augmented by ΔNErbB2, unaffected by the NBC inhibitor S0859, and further stimulated by EIPA in a manner potentiated by PI3K-Akt-inhibition. These findings demonstrate that NHE1 inhibition can enhance cancer cell motility, adding an important facet to the understanding of NHE1 in cancer.The Na+/H+ exchanger NHE1, but not the Na+, cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2 - Corrected ProofGitte Lauritzen, Christian-Martin Stock, Justine Lemaire, Stine F. Lund, Mie Frid Jensen, Britt Damsgaard, Katrine Seide Petersen, Maria Wiwel, Lone Rønnov-Jessen, Albrecht Schwab, Stine Falsig Pedersen10.1016/j.canlet.2011.11.023Cancer Letters (2012)2012-01-04Cancer Letters2012-01-04http://www.cancerletters.info/article/PIIS0304383511007701/abstract?rss=yesAbstract: IL-32 is a newly discovered cytokine. Recently, various reports suggest that it plays a role as a proinflammatory mediator and may be involved in several cancer carcinogenesis. However, IL-32 expression in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated the expression and role of IL-32α in hepatocellular carcinoma, because IL-32 was identified as an upregulated gene in hepatocellular carcinoma tissues compared to nontumorous regions using DNA microarray. IL-32α was overexpressed in tissue and serum from patients with HCC and localized in the cytoplasm and nucleus of hepatocellular carcinoma tumor cells. Moreover, secreted IL-32α concentration in the serum of patients with hepatocellular carcinoma was elevated as compared with those in the normal serum using a developed sandwich ELISA. Furthermore, IL-32α suppression in hepatocellular carcinoma decreased expression of phospho-p38 MAPK, NF-κB, and antiapoptotic protein Bcl-2 and induced expression of proapoptotic proteins as well as p53 and PUMA resulting in the suppression of cell growth and induction of intrinsic apoptosis. Based on our results, we suggest that IL-32α is involved in the progression of hepatocellular carcinoma and may be a useful biomarker for diagnosis and therapeutic target of hepatocellular carcinoma.Dysregulation of overexpressed IL-32α in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-κB and Bcl-2 - Corrected ProofYun Hee Kang, Mi-Young Park, Do-Young Yoon, Seung Ro Han, Chung Il Lee, Na Young Ji, Pyung-Keun Myung, Hee Gu Lee, Jae Wha Kim, Young Il Yeom, Ye Jin Jang, Dong Kuk Ahn, Jong Wan Kim, Eun Young Song10.1016/j.canlet.2011.12.023Cancer Letters (2012)2012-01-04Cancer Letters2012-01-04http://www.cancerletters.info/article/PIIS0304383511007567/abstract?rss=yesAbstract: Reactive oxygen species (ROS), the most prominent free radicals produced in cells, can have both beneficial and detrimental effects on them. Many genes are known to be involved in ROS regulation. P53 inducible gene 3 (PIG3 or TP53I3) was identified in an analysis of genes induced by p53 before the onset of apoptosis. It is a widely conserved gene between many species. Until now it has been shown to exert two disparate cellular roles. The first is that of ROS producer linked to p53 induced apoptosis. In this context, it exhibits a NADPH dependent reductase activity with orthoquinones. The second is that of a component of the DNA damage response pathway. While it is considered as a p53 dependent pro-apoptotic gene, it is rarely affected in cancer. This data does not support an anti-tumor activity. In the present review we present and discuss aspects on the regulation and function of this factor and how it is implicated in cancer. We conclude by proposing that PIG3 may possibly have a role in cancer cell survival.PIG3: A novel link between oxidative stress and DNA damage response in cancer - Corrected ProofAthanassios Kotsinas, Vimla Aggarwal, E-Jean Tan, Brynn Levy, Vassilis G. Gorgoulis10.1016/j.canlet.2011.12.009Cancer Letters (2012)2012-01-03Cancer Letters2012-01-03http://www.cancerletters.info/article/PIIS0304383511007579/abstract?rss=yesAbstract: Purposes: A lot of radiosensitizers have been developed. However, there are few to be available in the clinical setting. Thymidine phosphorylase inhibitor (TPI) regulates the phosphorolysis of thymidine to thymine and 2-deoxy-d-ribose-1-phosphate which is essential for tumor angiogenesis. The aim of this study is to evaluate whether TPI augments the radiotherapy for colorectal cancer in vitro and in vivo studies.Materials and methods: The cytotoxicity of TPI with irradiation on HT29 and HCT116 cells was examined using MTT- and colony formation assay. At 10days post-inoculation, HT29 bearing orthotopic model mice (n=28) were divided into four groups and orally treated with TPI- (50mg/kg/day for 2weeks), radiation (RT, 2Gy×4: Total 8Gy), their combination or the vehicle. The mechanisms underlying the efficacy were assessed genomically and immunohistochemically.Results: Compared to each single treatment, the combination of TPI and RT synergistically inhibited the cell viability in a time- and dose-dependent manner. In the HT-29 bearing mice, the combination of TPI and RT reduced the tumor growth compared with RT alone. Notably, the mRNA levels of VEGF, TGF-β and, Rad51 and the protein expressions of VEGF and CD34 were significantly lower in the combination than the others. Furthermore, the combination markedly increased the TUNEL-positive cells, suggesting that TPI augments the cancer cell death through inhibition of angiogenesis and DNA repair system in the radiotherapy.Conclusions: Our study first demonstrated that the combination of TPI and irradiation was effective in colon cancer. TPI would provide a promising therapeutic strategy as a radiosensitizer.Platelet-derived endothelial cell growth factor/thymidine phosphorylase inhibitor augments radiotherapeutic efficacy in experimental colorectal cancer - Corrected ProofTomohiko Miyatani, Nobuhiro Kurita, Tohru Utsunomiya, Takashi Iwata, Masanori Nishioka, Kozo Yoshikawa, Jun Higashijima, Hideya Kashihara, Chie Takasu, Masakazu Fukushima, Mitsuo Shimada10.1016/j.canlet.2011.12.010Cancer Letters (2012)2012-01-03Cancer Letters2012-01-03http://www.cancerletters.info/article/PIIS0304383511007609/abstract?rss=yesAbstract: Human oncofetal protein Cripto-1 (CR-1) is overexpressed in many types of cancers. CR-1 binds to cell surface Glypican-1 to activate Erk1/2 MAPK and Akt pathways leading to cell proliferation. However, we show that treatment with recombinant CR-1 reduces proliferation of HeLa cells by increasing the doubling time without triggering cell death or cell cycle arrest. Using a comparative study with U-87 MG cells, we show that the pro-proliferative pathway of CR-1 is not effective in HeLa cells due to lower expression of Glypican-1. Further we show that treatment with recombinant CR-1 increases PTEN in HeLa cells leading to downregulation of PI3K/Akt pathway. The anti-proliferative effect gets potentiated when the pro-proliferative pathway is blocked.Human recombinant Cripto-1 increases doubling time and reduces proliferation of HeLa cells independent of pro-proliferation pathways - Corrected ProofAsim Bikas Das, Pojul Loying, Biplab Bose10.1016/j.canlet.2011.12.013Cancer Letters (2012)2012-01-03Cancer Letters2012-01-03http://www.cancerletters.info/article/PIIS030438351100766X/abstract?rss=yesAbstract: The Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), the most common HIV/AIDS-associated tumor worldwide. Involvement of the oral cavity portends a poor prognosis for patients with KS, but mechanisms for KSHV regulation of the oral tumor microenvironment are largely unknown. Infiltrating fibroblasts are found with KS lesions, and KSHV establishes latent infection within human primary fibroblasts in vitro, but contributions for KSHV-infected fibroblasts to the KS microenvironment have not been previously characterized. Secretion of pro-migratory factors and intratumoral invasion are characteristics of tumor-associated fibroblasts (TAF) found in the microenvironment of non-viral malignancies. In the present study, we show that latent KSHV infection of primary human fibroblasts isolated from the oral cavity enhances their secretion of KS-promoting cytokines and intrinsic invasiveness through VEGF-dependent mechanisms. Moreover, we find that KSHV induces these effects through Sp1- and Egr2-dependent transcriptional activation of the Extracellular Matrix MetalloPRoteinase INducer (emmprin). These data implicate KSHV activation of emmprin in the induction of a “TAF-like” phenotype for oral fibroblasts in the KS microenvironment and support the potential utility of targeting TAFs and/or emmprin in the treatment of oral KS.Kaposi sarcoma-associated herpesvirus (KSHV) induces a functional tumor-associated phenotype for oral fibroblasts - Corrected ProofLu Dai, Zhiqiang Qin, Michael Defee, Bryan P. Toole, Keith L. Kirkwood, Chris Parsons10.1016/j.canlet.2011.12.019Cancer Letters (2012)2012-01-03Cancer Letters2012-01-03http://www.cancerletters.info/article/PIIS0304383511007324/abstract?rss=yesAbstract: Cervical cancer is the second leading cause of cancer deaths among women worldwide. High-Risk-Human Papillomaviruses (HR-HPVs) play an important etiologic role in the development of carcinoma of the uterine cervix. However, host factors are important in determining the outcome of genital HPV infection as most cervical precancerous lesions containing HR-HPVs do not progress to invasive carcinomas. Retinoids, acting through nuclear receptors (RARs, RXRs), play a crucial role in cervix development and homeostasis regulating growth and differentiation of a wide variety of cell types; indeed, they can inhibit cell proliferation, and induce cell differentiation or apoptotic cell death. Here we introduce a mouse model that develops spontaneously malignant cervical lesions allowing the study of the cooperative effect between HPV16E6E7 expression and the lack of RXRα in cervical cancer development. This model could be useful to study multistep carcinogenesis of uterine cervix tissue and might improve chemopreventive and chemotherapeutic strategies for this neoplasia.RXRα deletion and E6E7 oncogene expression are sufficient to induce cervical malignant lesions in vivo - Corrected ProofRodolfo Ocadiz-Delgado, Eduardo Castañeda-Saucedo, Arup K. Indra, Rogelio Hernandez-Pando, Pedro Flores-Guizar, Jose Luis Cruz-Colin, Felix Recillas-Targa, Guillermo Perez-Ishiwara, Luis Covarrubias, Patricio Gariglio10.1016/j.canlet.2011.11.031Cancer Letters (2011)2011-12-30Cancer Letters2011-12-30http://www.cancerletters.info/article/PIIS0304383511007348/abstract?rss=yesAbstract: Suppression of c-Myc is likely to induce cellular senescence in many tumors with unclear mechanisms. A proteomics survey indicated that high levels of BCL2-associated athanogene 2 (BAG2) were found in response to c-Myc repression in TRE293 cells. This observation led to the investigation into the role of BAG2 in c-Myc-induced senescence. The association of the c-Myc/SP1 complex with the BAG2 promoter verified the role of c-Myc/SP1 in regulating BAG2 transcription. Furthermore, high levels of BAG2 were found to induce p21CIP1-dependent senescence and subsequent carcinogenetic arrest, suggesting its possible role as an indirect activator of the p21CIP1 pathway.BAG2 is a target of the c-Myc gene and is involved in cellular senescence via the p21CIP1 pathway - Corrected ProofJu Zhang, Xiaomin Lou, Shangbin Yang, Shun He, Lei Yang, Mei Liu, Hongxia Zhu, Qiang Shan, Siyuan Su, Qimin Zhan, Ningzhi Xu, Siqi Liu10.1016/j.canlet.2011.11.033Cancer Letters (2011)2011-12-30Cancer Letters2011-12-30