Cancer Letters RSS feed: Current Issue. CANCER LETTERS is a journal providing rapid publication of full-length articles in the broad area of cancer research. The journal places emphasis on the molecular and cell biology of cancer, oncogenes, carcinogenesis, radiation biology, molecular pathology, hormones and cancer, viral oncology, biology of cancer and metastasis, molecular cytogenetics, epidemiology; and experimental therapeutics. The primary criterion for publication is interest to a multidisciplinary audience. Papers should be technically sound and substantiated by sufficient experimental detail. Clinical papers will be accepted if they contribute to the understanding of the basic mechanisms underlying disease. 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/?rss=yesElsevier Inc.en © 2009 Elsevier Ireland Ltd. All rights reserved. Cancer Letters0304-3835288228 February 2010 © 2009 Elsevier Ireland Ltd. All rights reserved. healthpermissions@elsevier.comhttp://www.cancerletters.info/article/PIIS0304383509004303/abstract?rss=yesAbstract: The full-length oestrogen receptor (ER) exists in most vertebrates as two separately encoded isoforms. ER splice variants represent truncated or otherwise modified versions of the full-length α or β isoforms of the parent receptor. ERα is found on chromosome 6q and encodes a 595 amino acid protein, while ERβ is found on chromosome 14q and encodes a 530 amino acid protein. These receptors possess differing ligand affinities, are differentially expressed in a tissue-specific fashion and may act antagonistically. Their altered expression has been implicated in the pathophysiology of a diverse range of conditions from cancer progression in hormone-responsive tissues to neurodegenerative disease. Variously co-expressed with full-length ERs, ER splice variants may have a positive or negative influence on transcription either by modifying the effect of the parent receptor or through their own intrinsic activity. To date, the vast majority of studies have used generic primers or antibodies against the full-length receptors and would not distinguish ER-mediated effects associated with various splice variants. Thus the evidence base of the influence of ER splice variants in normal developmental physiology and in the pathogenesis of disease is weak and greater understanding of their role will undoubtedly lead to new therapeutic strategies for disease intervention and treatment. This review aims to compile the current evidence for the presence of ER splice variants in humans, their physiological roles and clinical sequelae.Oestrogen receptor splice variants in the pathogenesis of diseaseSiân E. Taylor, Pierre L. Martin-Hirsch, Francis L. Martin10.1016/j.canlet.2009.06.017Cancer Letters 288, 2 (2010)2009-07-16Cancer Letters2009-07-162882S0304-3835(10)X0003-9Mini-reviews133148http://www.cancerletters.info/article/PIIS0304383509004479/abstract?rss=yesAbstract: Approximately 25% of head and neck squamous cell carcinoma (HNSCC) worldwide are associated with high-risk human papillomaviruses (HPV). HPV-positive HNSCCs have a more favorable outcome and greater response to therapy. While chronic HPV infection allows for the evolution of immune evasion mechanisms, viral antigens can still elicit an immune response. Moreover, a robust lymphocytic response is associated with better prognosis in a variety of tumor types including head and neck cancer. This article outlines several mechanisms whereby the observed improved response of HPV-positive tumors to radiotherapy may be related to enhancement of the immune response following radiotherapy.HPV-induced oropharyngeal cancer, immune response and response to therapyHa Linh Vu, Andrew G. Sikora, Shibo Fu, Johnny Kao10.1016/j.canlet.2009.06.026Cancer Letters 288, 2 (2010)2009-07-23Cancer Letters2009-07-232882S0304-3835(10)X0003-9Mini-reviews149155http://www.cancerletters.info/article/PIIS0304383509004583/abstract?rss=yesAbstract: Skp2 is one of the components of the E3 ubiquitin ligase which is required for the degradation of tumor suppressor p27. Overexpression of this oncogene is frequently found in human cancers and has been shown to be associated with poor prognosis. In addition to induce p27 degradation and enhance cellular proliferation, Skp2 also plays a role in promoting tumor metastasis. However, the underlying mechanism is unclear. In this study, we established Skp2-overexpressing stable transfectants from A549 human lung cancer cells. We found that these stable transfectants exhibited increased migratory and invasive abilities. In addition, expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was up-regulated. Enzymatic assay and gelatin zymography confirmed the increase of MMP-2 and MMP-9 activity and neutralization of these two MMPs by antibodies reduced cell invasion. Our results also revealed that Sp1 was involved in the induction of MMP-2 and MMP-9 by Skp2 because treatment of mithramycin or knockdown of Sp1 by small interference RNA attenuated their expressions. Collectively, we provide the first evidence that up-regulation of MMP-2 and MMP-9 is one of the mechanisms by which Skp2 promotes cell invasion.Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cellsWen-Chun Hung, Wei-Lung Tseng, Jentaie Shiea, Hui-Chiu Chang10.1016/j.canlet.2009.06.032Cancer Letters 288, 2 (2010)2009-07-22Cancer Letters2009-07-222882S0304-3835(10)X0003-9Regular Articles156161http://www.cancerletters.info/article/PIIS0304383509004595/abstract?rss=yesAbstract: Transforming growth factor (TGF)-β signaling makes a significant contribution to the pathogenesis of breast cancer bone metastasis. In other tumor types, TGF-β has been shown to promote tumor vascularity. Here, we report that inhibition of TGF-β significantly reduces microvessel density in mammary tumor-induced bone lesions, mediated by decreased expression of both vascular endothelial growth factor (VEGF) and monocyte chemotactic protein (MCP)-1, both known angiogenic factors. Cathepsin G upregulation at the tumor–bone interface has been linked to increased TGF-β signaling, and we also report that inhibition of Cathepsin G reduced tumor vascularity, as well as VEGF and MCP-1 expression.Cathepsin G-mediated enhanced TGF-β signaling promotes angiogenesis via upregulation of VEGF and MCP-1Thomas J. Wilson, Kalyan C. Nannuru, Mitsuru Futakuchi, Rakesh K. Singh10.1016/j.canlet.2009.06.035Cancer Letters 288, 2 (2010)2009-07-31Cancer Letters2009-07-312882S0304-3835(10)X0003-9Regular Articles162169http://www.cancerletters.info/article/PIIS0304383509004601/abstract?rss=yesAbstract: The study investigated the effects of the dopamine-somatostatin chimeric compound BIM-23A760 on cell proliferation and apoptosis in cultured cells from human non-functioning pituitary tumors (NFPTs). Both BIM-23A760 and the dopaminergic agonist BIM-53097 induced a significant inhibition of cell proliferation associated with increased p27 expression, together with a significant increase in caspase-3 activity. Conversely, null or marginal effects were elicited by somatostatin analogs. Moreover, BIM-23A760 and BIM-53097 induced ERK1/2 and p38 phosphorylation and the blockade of these pathways prevented both the antiproliferative and the pro-apoptotic effects of these drugs. In conclusions the chimeric compound BIM-23A760 is able to exert cytostatic and cytotoxic effects in NFPTs, these phenomena being mainly mediated by DR2D and involving ERK1/2 and p38 pathways activation.The dopamine–somatostatin chimeric compound BIM-23A760 exerts antiproliferative and cytotoxic effects in human non-functioning pituitary tumors by activating ERK1/2 and p38 pathwaysErika Peverelli, Luca Olgiati, Marco Locatelli, Paolo Magni, Marco Faustini Fustini, Giorgio Frank, Giovanna Mantovani, Paolo Beck-Peccoz, Anna Spada, Andrea Lania10.1016/j.canlet.2009.06.034Cancer Letters 288, 2 (2010)2009-07-21Cancer Letters2009-07-212882S0304-3835(10)X0003-9Regular Articles170176http://www.cancerletters.info/article/PIIS0304383509004625/abstract?rss=yesAbstract: Recent reports have shown that adiponectin has a suppressive effect on various types of malignancy. In order to clarify the role of adiponectin in colorectal carcinogenesis, we examined the effect of exogenous administration of adiponectin on intestinal polyp formation in C57BL/6J-ApcMin/+ mice, which possess a point mutation in the Apc gene. And we found that adiponectin treatment significantly decreased the number of adenomatous polyps, especially polyps larger than 2mm in diameter, in the small intestine. Two major receptors for adiponectin, AdipoR1 and AdipoR2, were expressed in adenomatous polyps, and their expression levels were not altered by adiponectin injection. In conclusion, adiponectin suppresses the growth of intestinal adenomas in the ApcMin/+ mice. Increasing the adiponectin level may be a new strategy for the prevention of colorectal cancer at an early step of carcinogenesis.Adiponectin suppresses tumorigenesis in ApcMin/+ miceKensuke Otani, Joji Kitayama, Koji Yasuda, Yasunori Nio, Masato Iwabu, Shinichi Okudaira, Junken Aoki, Toshimasa Yamauchi, Takashi Kadowaki, Hirokazu Nagawa10.1016/j.canlet.2009.06.037Cancer Letters 288, 2 (2010)2009-07-31Cancer Letters2009-07-312882S0304-3835(10)X0003-9Regular Articles177182http://www.cancerletters.info/article/PIIS0304383509004613/abstract?rss=yesAbstract: Because tumor necrosis factor-alpha (TNF-α) is well-known to induce inflammatory responses, thus its clinical use is limited in cancer treatment. Rosmarinic acid (RA), a naturally occurring polyphenol flavonoid, has been reported to inhibit TNF-α-induced NF-κB activation in human dermal fibroblasts. However, the precise mechanisms of RA have not been well elucidated in TNF-α-mediated anti-cancer therapy. In this study, we found that RA treatment significantly sensitizes TNF-α-induced apoptosis in human leukemia U937 cells through the suppression of nuclear transcription factor-kappaB (NF-κB) and reactive oxygen species (ROS). Activation of caspases in response to TNF-α was markedly increased by RA treatment. However, pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in response to combined treatment. RA also suppressed NF-κB activation through inhibition of phosphorylation and degradation of IκBα, and nuclear translocation of p50 and p65. This inhibition was correlated with suppression of NF-κB-dependent anti-apoptotic proteins (IAP-1, IAP-2, and XIAP). RA treatment also normalized TNF-α-induced ROS generation. Additionally, ectopic Bcl-2 expressing U937 reversed combined treatment-induced cell death, cytochrome c release into cytosol, and collapse of mitochondrial potential. These results demonstrated that RA inhibits TNF-α-induced ROS generation and NF-κB activation, and enhances TNF-α-induced apoptosis.Rosmarinic acid sensitizes cell death through suppression of TNF-α-induced NF-κB activation and ROS generation in human leukemia U937 cellsDong-Oh Moon, Mun-Ock Kim, Jae-Dong Lee, Yung Hyun Choi, Gi-Young Kim10.1016/j.canlet.2009.06.033Cancer Letters 288, 2 (2010)2009-07-21Cancer Letters2009-07-212882S0304-3835(10)X0003-9Regular Articles183191http://www.cancerletters.info/article/PIIS0304383509004637/abstract?rss=yesAbstract: A growing body of evidence suggests the inhibition of NFκB as a strategy to induce cell death in tumor cells. In this work, we evaluated the effects of the pharmacological NFκB inhibitors BAY117082 and MG132 on leukemia cells apoptosis. BAY117082 and MG132 presented potent apoptotic effects compared to inhibitors of MAPKs, EGFR, PI3K/Akt, PKC and PKA signaling pathways. Non-tumor peripheral blood cells were insensitive to BAY117082 and MG132 apoptotic effects. BAY117082 and MG132-induced apoptosis was dependent on their ability to increase ROS as a prelude to mitochondria membrane potential (MMP) depolarization, permeability transition pore opening and cytochrome c release. Antioxidants blocked MG132 and BAY117082 effects on ROS, MMP and cell death. Although apoptotic markers as phosphatidylserine externalization, chromatin condensation and sub-G1 were detected in BAY117082-treated cells, caspases activation did not occur and apoptosis was insensitive to caspase inhibitors, suggesting a caspase-independent mechanism. In contrast, MG132 induced classical apoptosis through ROS-mitochondria and subsequent caspase-9/caspase-3 activation. At sub-apoptotic concentrations, BAY117082 and MG132 arrested cells in G2/M phase of the cell cycle and blocked doxorubicin-induced NFκB, which sensitized doxorubicin-resistant cells. Data suggest that the NFκB inhibitors MG132 and BAY117082 are potential anti-leukemia agents.The pharmacological NFκB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activationAlfeu Zanotto-Filho, Andrés Delgado-Cañedo, Rafael Schröder, Matheus Becker, Fábio Klamt, José Cláudio Fonseca Moreira10.1016/j.canlet.2009.06.038Cancer Letters 288, 2 (2010)2009-07-31Cancer Letters2009-07-312882S0304-3835(10)X0003-9Regular Articles192203http://www.cancerletters.info/article/PIIS0304383509004777/abstract?rss=yesAbstract: We investigated the molecular effects of 3,4,2′,4′-tetrahydroxychalcone (butein) treatment in two human hepatoma cancer cell lines–HepG2 and Hep3B. Butein treatment inhibited cancer cell growth by inducing G2/M phase arrest and apoptosis. Butein-induced G2/M phase arrest was associated with increased ATM, Chk1, and Chk2 phosphorylations and reduced cdc25C levels. Additionally, butein treatment enhanced inactivated phospho-Cdc2 levels, reduced Cdc2 kinase activity, and generated reactive oxygen species (ROS) that was accompanied by JNK activation. The extent of butein-induced G2/M phase arrest significantly decreased following pretreatment with N-acetyl-l-cysteine or glutathione and following JNK phosphorylation reduction by SP600125. Both N-acetyl-l-cysteine and glutathione also decreased butein-mediated apoptosis. Taken together, these results imply a critical role of ROS and JNK in the anticancer effects of butein.Butein induces G2/M phase arrest and apoptosis in human hepatoma cancer cells through ROS generationDong-Oh Moon, Mun-Ock Kim, Yung Hyun Choi, Jin Won Hyun, Weon Young Chang, Gi-Young Kim10.1016/j.canlet.2009.07.002Cancer Letters 288, 2 (2010)2009-07-30Cancer Letters2009-07-302882S0304-3835(10)X0003-9Regular Articles204213http://www.cancerletters.info/article/PIIS0304383509004911/abstract?rss=yesAbstract: Urinary trypsin inhibitor (UTI), an inhibitor of urokinase plasminogen activator relevant to proteolytic processing from the inactive into the active form of platelet-derived growth factor-D (PDGF-D) to activate PDGF-ββ receptor (PDGF-ββR), inhibited fetal bovine serum-stimulated migration of human malignant mesothelioma, with the extent varying among the cell types. The more effective inhibition was found in NCIH-2052 and -2452 cells, with the higher expression of PDGF-ββR. The results of the present study suggest that UTI suppresses malignant mesothelioma cell migration by neutralizing active dimmer of PDGF-D (PDGF-DD)/PDGF-ββR-mediated signal transduction.Urinary trypsin inhibitor suppresses migration of malignant mesotheliomaTakahiro Yaguchi, Masakazu Muramoto, Takashi Nakano, Tomoyuki Nishizaki10.1016/j.canlet.2009.07.003Cancer Letters 288, 2 (2010)2009-08-06Cancer Letters2009-08-062882S0304-3835(10)X0003-9Regular Articles214218http://www.cancerletters.info/article/PIIS0304383509004935/abstract?rss=yesAbstract: The effects of ligand activation of PPARβ/δ were examined in the mouse mammary tumor cell line (C20). Expression of PPARβ/δ was markedly lower in C20 cells as compared to the human non-tumorigenic mammary gland derived cell line (MCF10A) and mouse keratinocytes. Ligand activation of PPARβ/δ in C20 cells caused upregulation of the PPARβ/δ target gene angiopoietin-like 4 (Angptl4). Inhibition of C20 cell proliferation and clonogenicity was observed following treatment with GW0742 or GW501516, two highly specific PPARβ/δ ligands. In addition, an increase in apoptosis was observed in C20 cells cultured with 10μM GW501516 that preceded the observed inhibition of cell proliferation. Results from this study show that proliferation of the C20 mouse mammary gland cancer cell line is inhibited by ligand activation of PPARβ/δ due in part to increased apoptosis.Ligand activation of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits cell growth in a mouse mammary gland cancer cell lineJennifer E. Foreman, Arun K. Sharma, Shantu Amin, Frank J. Gonzalez, Jeffrey M. Peters10.1016/j.canlet.2009.07.006Cancer Letters 288, 2 (2010)2009-08-06Cancer Letters2009-08-062882S0304-3835(10)X0003-9Regular Articles219225http://www.cancerletters.info/article/PIIS0304383509004947/abstract?rss=yesAbstract: Cellular senescence is an important tumor suppression process under diverse oncogenic conditions, entering a state of irreversible growth arrest to prevent damaged cells from undergoing aberrant proliferation. Developing a means of evading senescence thus seems to be a fundamental task that all cancer cells should solve early on. Here, we show that an oncogenic X protein of hepatitis B virus (HBx) overcomes cellular senescence provoked by a universal premature senescence inducer, H2O2, in human hepatoma cells, as demonstrated by impaired induction of senescence-associated biomarkers, including morphological change, G1 arrest, and β-galactosidase activity, in the presence of HBx. HBx induced DNA hypermethylation of p16INK4a promoter and subsequently interfered action of transcription factors like Ets1 and Ets2 activated by H2O2 through the p38MAPK pathway, resulting in inhibition of its transcription. Down-regulation of p16INK4a expression by HBx subsequently led to activation of G1-CDKs, phosphorylation of Rb, activation of E2F1, and finally evasion from G1 arrest induced by H2O2. Levels of another senescence regulator, p21waf1, however, were not affected by HBx under our senescence-inducing conditions. In addition, the potentials of HBx to inactivate Rb and subsequently inhibit cellular senescence almost completely disappeared when levels of p16INK4a were recovered either by exogenous complementation or inhibition of the promoter hypermethylation. To our knowledge, our present study represents the first report that an oncogenic virus evades cellular senescence through epigenetic down-regulation of p16INK4a expression.Hepatitis B virus X protein overcomes stress-induced premature senescence by repressing p16INK4a expression via DNA methylationYe-Jin Kim, Jin Kyu Jung, Sun Young Lee, Kyung Lib Jang10.1016/j.canlet.2009.07.007Cancer Letters 288, 2 (2010)2009-08-05Cancer Letters2009-08-052882S0304-3835(10)X0003-9Regular Articles226235http://www.cancerletters.info/article/PIIS0304383509004959/abstract?rss=yesAbstract: We previously demonstrated that the PPARγ agonist Troglitazone (TRG), a potent antiproliferative agent, in combination with the anthracycline antibiotic Doxorubicin (DOX), is an effective killer of multiple drug resistant (MDR) human cancer cells. Cell killing was accompanied by increased global histone H3 acetylation. Presently, we investigated the epigenetic and cell killing effects of TRG in estrogen receptor (ER) positive MCF7 breast cancer cells. MCF7 cells were treated with the Thiazolidinediones (TZDs) TRG and Ciglitazone (CIG), the non-TZD PPARγ agonist 15PGJ2, and the histone deacetylase inhibitors (HDACi’s) Trichostatin A (TSA), sodium butyrate and PXD101. Using MTT cell viability assays, Western analyzes and mass spectrometry, we showed a dose-dependent increase in cell killing in TRG and HDACi treated cells, that was associated with increased H3 lysine 9 (H3K9) and H3K23 acetylation, H2AX and H3S10 phosphorylation, and H3K79 mono- and di-methylation. These effects were mediated through an ER independent pathway. Using HDAC activity assays, TRG inhibited HDAC activity in cells and in cell lysates, similar to that observed with TSA. Furthermore, TRG and TSA induced a slower migrating HDAC1 species that was refractory to HDAC2 associations. Lastly, TRG and the HDACi’s decreased total and phosphorylated AKT levels. These findings suggest that TRG’s mode of killing may involve downregulation of PI3K signaling through HDAC inhibition, leading to increased global histone post-translational modifications.Troglitazone inhibits histone deacetylase activity in breast cancer cellsG.F. Davies, A.R. Ross, T.G. Arnason, B.H.J. Juurlink, T.A.A. Harkness10.1016/j.canlet.2009.07.011Cancer Letters 288, 2 (2010)2009-08-21Cancer Letters2009-08-212882S0304-3835(10)X0003-9Regular Articles236250http://www.cancerletters.info/article/PIIS0304383509004960/abstract?rss=yesAbstract: The kringle domain of urokinase-type plasminogen activator (UK1) has anti-angiogenic and anti-tumor effects. Celecoxib, an inhibitor of cyclooxygenase type 2, also suppresses angiogenesis and tumor growth. To look for potential additive effects in their activities, we examined the anti-angiogenic and anti-tumor effects of the combination of UK1 and celecoxib for malignant gliomas. In vitro, the combination of UK1 and celecoxib enhanced inhibition of proliferation, migration, and tube formation of endothelial cells, although showing no enhancement of inhibition of U87 cell growth. However, in vivo models, combination treatment of intracerebral U87 malignant glioma xenografts in nude mice with UK1 (10mg/kg/day) and celecoxib (10mg/kg/day) at lower doses resulted in even more potent inhibition of tumor growth than each monotherapy (by 81% compared to untreated tumors), with drastic decrease of the expression of angiogenesis-related factors and increase of apoptosis in the tumor tissues. Interestingly, UK1 inhibited VEGF or bFGF-induced phosphorylation of ERK1/2 in ECs, whereas celecoxib showed no such effects. However, celecoxib inhibited U87 cell growth and directly suppressed their VEGF production. Therefore, our data suggest that combined use at low doses of UK1 and celecoxib with different anti-angiogenic mechanisms provides a desirable strategy for anti-glioma therapy.Enhancement of anti-tumor activity by low-dose combination of the recombinant urokinase kringle domain and celecoxib in a glioma modelChung Kwon Kim, Young Ae Joe, Suk-Keun Lee, Eun-Kyoung Kim, Eunju O, Hyun-Kyung Kim, Bae Jun Oh, Sung Hee Hong, Yong-Kil Hong10.1016/j.canlet.2009.07.008Cancer Letters 288, 2 (2010)2009-08-07Cancer Letters2009-08-072882S0304-3835(10)X0003-9Regular Articles251260