Critical role of NF-κB in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and in spite of intense efforts there are limited therapeutic options for patients with PDAC. PDACs harbor a high frequency of Kras mutations and other driver mutations that lead to altered signaling pathways and contribute to therapeutic resistance. Importantly, constitutive activation of nuclear factor κB (NF-κB) is frequently observed in PDAC. An increasing body of evidence suggests that both classical and non-classical NF-κB pathways play a crucial role in PDAC development and progression. In this review, we update the most recent advances regarding different aspects of NF-κB involvement in PDAC development and progression, emphasizing its potential as a therapeutic target and the need to discover pathway-specific cytosolic NF-κB regulators which could be used to design novel therapeutic strategies for PDAC.

Figure 1. A proposed working model illustrates the potential mechanism through which KrasG12D oncogenic signaling induces positive feedback loops of IL-1α and p62 to sustain constitutive IKKβ/NF-κB activation in PDAC development

KrasG12D induces the secretion of IL-1α, which further leads to the ubiquitination of TRAF6 and activation of IKKβ. This would further activate NF-κB to induce its target genes, including p62. The p62 protein in turn will positively regulate TRAF6 ubiquitination and lead to the constitutive NF-κB activation and PDAC development (Adapted from Ref. 26).

Figure 2. Interactions of NF-κB signaling pathway in pancreatic cancer (PC)

As indicated in the diagram, both classical and non-classical NF-κB pathways interact with a number of signaling pathways to remain constitutively activated in pancreatic cancer cells and promotes tumorigenesis and metastasis.