Mini-reviewNF-κB in pancreatic cancer: Its key role in chemoresistance
Introduction
Pancreatic cancer is considered one of the most malignant and aggressive cancers [1]. The overall five-year survival rate for pancreatic cancer ranges from 2% to 9% and is approximately 8% in both developed and developing countries [2]. Frustrating delays in the discovery or diagnosis which reduces the probability of complete resection underscore the necessary of chemotherapy for most pancreatic cancer cases. Disappointingly, there is a lack of sufficiently effective agents for the treatment of pancreatic cancer [3]. Many studies reported that because of complex pathways and regulator interactions in cancer cells, the use of these available agents eventually resulted in drug resistance after they are administered for a certain period of time [4]. Mechanisms of chemoresistance are still not clearly described, although there have been many studies that investigate how chemoresistance arises and which signaling pathways are altered during this process.
The nuclear factor kappa B (NF-κB) family of transcription factors was found to play an important role in this process, which consists of five members: RelA (p65), RelB, c-Rel, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) [5,6]. All of these proteins share a Rel homology domain (RHD) that regulates the development and progression of cancers by providing a binding domain for NF-κB-specific DNA motifs and characterizing NF-κB proteins [7]. NF-κB transcription factors could be prevented from translocating to the nucleus by the inhibitors of NF-κB (IκB), due to the masking of their nuclear localization signals (NLS), and are thus maintained in a latent and inactive state in the cytoplasm [8]. In human cells, NF-κB transcription factors are thought to be activated by the classical pathway and the alternative pathway. In the classical pathway, radiation, stress and exposure to cytokines activate the β subunit of the IκB kinase (IKK) complex, which results in the phosphorylation of IκB proteins at the N terminus, leading to polyubiquitination and degradation by proteasomes [9,10]. Thus, anti-apoptosis induced by the targeting genes such as inhibitors of apoptosis proteins (IAPs) and tumor necrosis factor (TNF) receptor-associated factor (TRAF) protein family and inflammation activities involved by cyclooxygenase-2 (COX-2) and interleukin-1 (IL-1) are activated. In the alternative pathway, the phosphorylation of p100 in its C-terminal region through the IKKα complex, activated by NF-κB-inducing kinase (NIK) in response to a subset of lymphotoxin β receptors or CD40 ligands, leads to the ubiquitination and processing of p100 to produce p52 [10]. Then, p52 combines with RelB to form the p52-RelB complexes, translocates into the nucleus and induces the expression of NF-κB target genes, such as B-cell-activating factor and stomal derived factor-1α, which plays a key role in survival, B-cell development, myelopoiesis and lymphopoiesis. Due to its interactions with numerous factors and proteins, NF-κB is considered as a key signaling mediator that contributes to the development and progression of various cancers [11]. It's also a crucial component in the acquisition of drug resistance in tumors, including pancreatic cancer which usually has high expressions of NF-κB [12].
In this review, we introduced the pivotal functions of NF-κB in the chemoresistance of pancreatic cancer in detail and also its other functions briefly at the same time.
Section snippets
NF-κB signaling pathway and the biological behavior of pancreatic cancer
As mentioned above, NF-κB signaling pathway plays important roles in the development and progression of pancreatic cancer. We summarize the potential cytokines, signaling pathways and agents that inhibit the activation of NF-κB and other members of this signaling pathway in Fig. 1 and Table 1.
NF-κB signaling pathway and chemotherapeutic resistance in pancreatic cancer
Chemotherapy has continued to be important for the treatment of and improvement in the survival of pancreatic cancer patients over the past several decades. Gemcitabine has been regarded as a first-line agent for pancreatic cancer since it was demonstrated to prolong survival by 5.65 months in a milestone clinical trial in 1997 [63]. Additionally, it has been recommended as an adjuvant regimen for resectable pancreatic cancer to enhance disease-free and overall survival as demonstrated in a
Conclusion
Our review highlights the biological behavior and role of NF-κB in pancreatic cancer cells. Since it is associated with several hallmarks of cancer, NF-κB plays important roles in oncogenesis and the development, progression and chemoresistance of pancreatic cancer. In particular, both the constitutive and chemotherapeutic agent-induced activation of NF-κB have been shown to cause chemoresistance in pancreatic cancer, which indicates a fact that targeting the NF-κB signaling pathway may help
Author contributions
T.Z. and Y.Z. contributed to the conception and design of the study; Q.L., G.Y. wrote the main text of the manuscript; and M.F., S.Z., Z.C. and J.Q. prepared the figures and tables. L.Y., Y.H. and L.Z. provided advice regarding the paper. All authors reviewed the manuscript.
Conflicts of interest
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, NF-κB in Pancreatic Cancer: Its Key Role in Chemoresistance.
Acknowledgments
The authors acknowledge the contribution of all investigators at the participating study sites. This study was supported by grants from the National Natural Science Foundation of China (No. 81472327), the Major State Basic Research Development Program of China (973 Program, No. 2014CB542300), the National Science and Technology Support Program of China (No. 2014BAI09B11), the Chinese Academy Medical Science Innovation Fund for Medical Sciences (No. 2016-I2M-1-001) and the PUMC Youth Fund and
References (88)
- et al.
Pancreatic cancer
Lancet
(2016) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma
Canc. Cell
(2012) - et al.
NEMO peptide inhibits the growth of pancreatic ductal adenocarcinoma by blocking NF-kappaB activation
Canc. Lett.
(2017) - et al.
Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis
Biochem. Biophys. Res. Commun.
(2013) - et al.
Apigenin potentiates the growth inhibitory effects by IKK-beta-mediated NF-kappaB activation in pancreatic cancer cells
Toxicol. Lett.
(2014) - et al.
Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis
Canc. Cell
(2015) - et al.
Gastrin regulates ABCG2 to promote the migration, invasion and side populations in pancreatic cancer cells via activation of NF-kappaB signaling
Exp. Cell Res.
(2016) - et al.
Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-kappaB signaling pathway
Mol. Canc.
(2017) - et al.
Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer
Lab. Invest. J. Tech. Meth. Pathol.
(2016)
Matrix metalloproteinases: regulators of the tumor microenvironment
Cell
Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis
Gastroenterology
TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells
Hepatobiliary Pancreat. Dis. Int. HBPD INT
Glycogen synthase kinase-3 (GSK3) inhibition induces prosurvival autophagic signals in human pancreatic cancer cells
J. Biol. Chem.
Chronic pancreatitis: a path to pancreatic cancer
Canc. Lett.
Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors
Canc. Lett.
Angiogenesis in pre-malignant conditions
Eur. J. Canc.
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy
Trends Pharmacol. Sci.
Hypoxia-inducible factor-dependent repression of equilibrative nucleoside transporter 2 attenuates mucosal inflammation during intestinal hypoxia
Gastroenterology
Combination chemotherapy of serine protease inhibitor nafamostat mesilate with oxaliplatin targeting NF-kappaB activation for pancreatic cancer
Canc. Lett.
Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution
J. Nutr. Biochem.
Cancer statistics, 2017
CA A Cancer J. Clin.
Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies
Drug Des. Dev. Ther.
Adjuvant therapy in pancreatic cancer
World J. Gastroenterol.
RelB, a member of the Rel/NF-kappa B family of transcription factors
Braz. J. Med. Biol. Res. Rev. Brasileira de Pesquisas Medicas e Biologicas
The complexity of NF-kappaB signaling in inflammation and cancer
Mol. Canc.
Rel/NF-kappa B transcription factors and I kappa B inhibitors: evolution from a unique common ancestor
Oncogene
Protein-binding sites in Ig gene enhancers determine transcriptional activity and inducibility
Science
Critical role of NF-kappaB in pancreatic cancer
Oncotarget
Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells
Canc. Biol. Ther.
Secretion of cytokines and growth factors as a general cause of constitutive NFkappaB activation in cancer
Oncogene
Nuclear factor-kappaB in cancer development and progression
Nature
Signaling pathways in pancreatic cancer
Crit. Rev. Eukaryot. Gene Expr.
Prognostic value of p21-activated kinase 4 in resected pancreatic cancer
APMIS: APMIS (Acta Pathol. Microbiol. Immunol. Scand.)
p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-kappaB pathway
Oncotarget
p21-Activated kinase 4 (PAK4) as a predictive marker of gemcitabine sensitivity in pancreatic cancer cell lines
Cancer Res. Treat. Off. J. Kor. Canc. Assoc.
IL1 receptor antagonist inhibits pancreatic cancer growth by abrogating NF-kappaB activation
Clin. Canc. Res. Off. J. Am. Assoc. Canc. Res.
Growth inhibition of pancreatic cancer cells by histone deacetylase inhibitor belinostat through suppression of multiple pathways including HIF, NFkB, and mTOR signaling in vitro and in vivo
Mol. Carcinog.
Alphav integrin: a new gastrin target in human pancreatic cancer cells
World J. Gastroenterol.
Inhibition of invasion in pancreatic cancer cells by conjugate of EPA with beta(3,3)-pip-OH via PI3K/Akt/NF-kB pathway
ACS Med. Chem. Lett.
Axon guidance factor SLIT2 inhibits neural invasion and metastasis in pancreatic cancer
Canc. Res.
Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70
Canc. Res.
Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-kappaB downregulation, International journal of cancer
J. Int. Canc
A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer
Sci. Transl. Med.
Cited by (0)
- 1
These authors contributed equally to this study.