NF-κB and Pancreatic Cancer; Chapter and Verse

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world's most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials.

Keywords: NF-κB; PDAC; Smac mimetics; inflammation; pancreatic cancer; pancreatitis; therapy; tumor microenvironment.

Figure 1

Structural Domain organisation of the Rel/NF-κB signalling pathway components. The mammalian NF-κB family members share a conserved Rel homology domain (RHD), nuclear localisation sequence (NLS) and a transcriptional activation domain (TAD) (A). The glycine rich region (GRR) in the p105 and p100 proteins signal for restricted proteasomal processing to generate the p50 and p52 proteins, respectively (black lines). (B) The transcriptional activity of NF-κB is regulated by the IκB proteins; IκBα, IκBβ, IκBɛ, IκBζ, BCL-3, IκBNS, p100, and p105. (C) The IKK complex consists of the catalytic kinase subunits IKKα (IKK1), IKKβ (IKK2) and the regulatory subunit NEMO (IKKγ). Both IKKα and IKKβ possess a helix-loop-region (HLH) and a leucine zipper domain (LZ), which mediate both homo- and hetero-dimerization of these proteins. IKKα and IKKβ interact with NEMO through their NEMO binding domain (NBD), which contains coiled coil domains (CC) and a leucine zipper (ZF). Protein domains typifying each protein family; (A) Ankyrin repeat domain; (DD) death domain; (GRR) glycine-rich region; (PEST) proline-rich, glutamic acid-rich, serine-rich, and threonine-rich.

Figure 2

NF-κB/DNA complex structures. (A) Ribbon representation of the crystal structure of murine NF-κB1 (p50, residues 39–364, green) and RelA (p65, residues 19–291, orange) heterodimer bound to the kappaB DNA of the intronic enhancer of the immunoglobulin light-chain gene (blue/red) [71] generated by Mac PyMol from PDB ID 1VKX. (B) Ribbon representation of the crystal structure of human IκBα (residues 67–302, blue) bound to the murine NF-κB1 (p50, dimerisation domain residues 245–363, green) and murine RelA (p65, residues 19–304, orange heterodimer [72]) from PDB ID 1IKN.

Figure 3

The canonical and non-canonical NF-κB signalling pathways. Simplified diagrams of NF-κB signaling, (left): Stimulation of TOLL-like receptors (TLRs), infection or ligand binding (e.g., TNF) to cell surface receptors (e.g., TNF-R1) trigger c-REL, NF-κB1 (p105/p50) or p65/RelA and activation of the inhibitory IKK (IκB kinase) complex. This complex is recruited to adaptor proteins (TRAFs or RIP kinases (dashed arrows)), activating the IKK complex, resulting in phosphorylation of Iκ proteins, priming them for ubiquitination and proteasome degradation. NF-κB dimers (NF-κB1 (p50) and c-Rel pairing with RelA/p65) enter the nucleus and bind to target gene κB sites. The non-canonical NF-κB pathway, (right); is activated by members of the TNF-R family (e.g., LTβR, BAFFR, CD40, RANK) by NIK mediated activation of an IKK kinase complex which in turn phosphorylates p100-NF-κB2 leading to its limited proteolysis to produce the p52 form of NF-κB2. Entry of p52-NF-κB2/RELB heterodimers into the nucleus follows, regulating target gene expression. AgR (antigen receptor), LTβR (lymphotoxin β receptor), BAFF/R (B cell activating factor), RANK (receptor activator for NF-κB).

Figure 4

The role of NF-κB from Pancreatic Ductal Adenocarcinoma (PanIN) to Pancreatic Ductal Adenocarcinoma (PDAC) in a step-wise model.

Figure 5

NF-κB; activation and inhibition. Simplified schematic diagram of the canonical and non-canonical NF-κB and TLR/IL-1R pathways. Red arrows indicate intervention points within each pathway for NF-κB and other pathway inhibitors and red boxes list examples of drugs. Many inhibitors are broad range (both pathways), others target a precise stage of NF-κB activation and yet others target multiple stages of NF-κB or TLR/IL-1R signaling.