Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice

Abstract

The majority of human pancreatic cancers have activating mutations in the KRAS proto-oncogene. These mutations result in increased activity of the NF-κB pathway and the subsequent constitutive production of proinflammatory cytokines. Here, we show that inhibitor of κB kinase 2 (Ikk2), a component of the canonical NF-κB signaling pathway, synergizes with basal Notch signaling to upregulate transcription of primary Notch target genes, resulting in suppression of antiinflammatory protein expression and promotion of pancreatic carcinogenesis in mice. We found that in the Kras G12D Pdx1-cre mouse model of pancreatic cancer, genetic deletion of Ikk2 in initiated pre-malignant epithelial cells substantially delayed pancreatic oncogenesis and resulted in downregulation of the classical Notch target genes Hes1 and Hey1. Tnf-α stimulated canonical NF-κB signaling and, in collaboration with basal Notch signals, induced optimal expression of Notch targets. Mechanistically, Tnf-α stimulation resulted in phosphorylation of histone H3 at the Hes1 promoter, and this signal was lost with Ikk2 deletion. Hes1 suppresses expression of Pparg, which encodes the antiinflammatory nuclear receptor Pparγ. Thus, crosstalk between Tnf-α/Ikk2 and Notch sustains the intrinsic inflammatory profile of transformed cells. These findings reveal what we believe to be a novel interaction between oncogenic inflammation and a major cell fate pathway and show how these pathways can cooperate to promote cancer progression.

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

“…As described above, NFkB signaling may be activated by oncogenic Kras. The activation of NFkB can activate Notch signaling, and Notch signaling synergizes with Kras to accelerate PDAC development (84). In addition, activated Notch signaling suppresses the anti-inflammatory transcription factor peroxisome proliferator-activated receptorg, leading to constitutive production of inflammatory mediators by malignant cells in PDAC (84).…”

“…The activation of NFkB can activate Notch signaling, and Notch signaling synergizes with Kras to accelerate PDAC development (84). In addition, activated Notch signaling suppresses the anti-inflammatory transcription factor peroxisome proliferator-activated receptorg, leading to constitutive production of inflammatory mediators by malignant cells in PDAC (84). Therefore, Notch seems to be of significance in pancreatic carcinogenesis, and cross-talks among Kras, NFkB, Notch, and COX-2 in cellular signaling might contribute to the molecular pathogenesis of pancreatic cancer.…”

Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells

“…7C). Nevertheless, this complex CD8aaTCRab siIEL phenotype could also be because of the extensive cross talk of the Notch-signaling pathway with numerous other pathways such as TGF-b (52), NF-kb (53), and Wnt in a cell-and/or tissue-specific manner. For instance, T cell-specific loss of either TGF-bRI or Smad3 leads to selective loss of CD8aaTCRab IELs in the small intestinal epithelium (25).…”

Crosstalk between the Notch signaling pathway and non‑coding RNAs in gastrointestinal cancers (Review)

“…It has been demonstrated that JAG1 expression levels are significantly upregulated in tumor tissues when compared with normal tissues, and miR-224 regulates JAG1 expression by binding JAG1 mRNA at its 3'UTR (81). Notch signaling is well-documented to be associated with various pancreatic diseases (81,82), including tumorigenesis and tumor progression (81). Therefore, it may be speculated that miR-224 has the capacity to stimulate oncogenesis in MCNs through the negative control of JAG1 (81).…”