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.

Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers

“…Furthermore, bacterial ablation increased PD-1 expression on effector T cells [69]. The binding of micro-organism-associated molecular patterns to specific Toll-like receptors leads to the activation of NF-κB and MAPK pathways, key promoters of pancreatic-cancer oncogenesis [70][71][72].…”

Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers

“…We, and others, have shown that smac-mimetics function by instigating auto-ubiquitylation and proteasomal degradation of cIAP1 and cIAP2 ( 284 , 285 , 288 , 289 ), which in the presence of a stimulus such as TNF, chemotherapy or TLR ligand, results in the formation of a RIPK1/caspase-8 complex, followed by caspase-8 cleavage and the induction of tumor cell death ( 281 , 285 , 290 , 291 ). A number of smac-mimetic compounds have been developed and due to their limited anti-cancer activities when used as single agents are now being tested in combination with immunotherapy and/or chemotherapy ( 6 , 281 , 282 ). For example, a trial reported in 2020, using Debio 1143 in combination with chemo-radiotherapy was the first drug combination in more than three decades to significantly improve overall survival in high risk HNSCC (includes OSCC) patients (ClinicalTrials.gov NCT02022098) ( 237 ) and a phase III trial is currently recruiting (ClinicalTrials.gov NCT04459715) ( Table 1 ) .…”

“…The term cytokine encompasses interleukins, chemokines, interferons and tumour necrosis factors and all bind to corresponding receptors to activate cellular signaling pathways, including two related and evolutionary conserved signature signaling entities, the Janus Kinases (JAK: a family of tyrosine kinases) and the Signal Transducer and Activator of Transcription (STAT) protein family, which together constitute the JAK-STAT signaling pathway and has been studied in great detail ( 1 – 5 ). Another well studied pathway activated by cytokines is the NF-κB pathway, a family of inducible transcription factors, required in both innate and adaptive immunity to rapidly activate cellular responses ( 6 , 7 ). Over 50 cytokines can signal through the JAK-STAT pathway, mediated by JAK-mediated phosphorylation, ultimately regulating a signaling cascade upstream of multiple cellular activities ( 8 – 13 ).…”

NF‐κB as a regulator of cancer metastasis and therapy response: A focus on epithelial–mesenchymal transition

“…Then, N‐terminal part of p100 that shows NF‐κB2 p52 translocates into the nucleus by binding to RelB (Cildir et al, 2016; Feige et al, 2018). More details about NF‐κB signaling can be found in recent reviews (Figure 1) (Espinosa & Marruecos, 2021; Gilmore, 2021; Silke & O'Reilly, 2021).…”