Cancer Letters

Cancer Letters

Volume 421, 1 May 2018, Pages 127-134
Cancer Letters

Mini-review
NF-κB in pancreatic cancer: Its key role in chemoresistance

https://doi.org/10.1016/j.canlet.2018.02.011Get rights and content

Highlights

  • NF-κB activation influences biological behaviors and chemoresistance in PC cells.

  • Activation of NF-κB responding to chemotherapy results in inducible chemoresistance.

  • Side effects need be considered when inhibiting NF-κB in PC adjuvant therapy.

Abstract

Pancreatic cancer is considered a lethal disease with a high mortality and an extremely low five-year survival rate. Chemotherapy plays a pivotal role in pancreatic cancer treatment both in an adjuvant setting after complete resection and in the case of unresectable metastatic disease. However, none of the available combination chemotherapy regimens has resulted in satisfactory survival outcomes. Recent studies have revealed that both constitutive and induced activation of nuclear factor kappa B (NF-κB) in pancreatic cancer cells are closely associated with cell proliferation, invasion, anti-apoptosis, inflammation, angiogenesis and chemotherapeutic resistance. Therefore, NF-κB inhibitors in combination with cytotoxic compounds have been reported as novel agents that improve chemotherapy sensitivity in pancreatic cancer. In this review, we outline recent developments in the understanding of the role of the NF-κB signaling pathway and its associated genes in the progression of pancreatic cancer and highlight some potentially effective strategies for pancreatic cancer treatment.

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

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