#Taghon notched up a level full
#Taghon notched up a level series

This leads to proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). Classical activation of Notch signaling is triggered by ligation of Notch receptors and ligands. Interestingly, in many types of cancer, including pancreatic cancer, the NF-κB and Notch pathways are activated ( 12– 15). However, the implication of the pathway in pancreatic cancer has so far been unexplored.

#Taghon notched up a level series

A series of studies has indicated a requirement of Ikk2 and p65 in both murine and human Kras-induced transformation of lung epithelial cells and in models of inflammation-induced carcinogenesis ( 7, 8, 10, 11). This releases the p65/p50 NF-κB heterodimer, allowing its nuclear translocation and promoter binding for inflammatory gene transcription. During canonical NF-κB signaling, inflammatory stimuli including cytokines such as Tnf-α generate signals that converge at the Ikk complex, phosphorylating Ikk2, which in turn phosphorylates the inhibitory molecule inhibitor of κB (IκB), resulting in its proteasomal degradation. NF-κB activation is regulated through the inhibitor of κB kinase (Ikk) complex, which consists of two catalytic subunits, Ikk1 and Ikk2 and the regulatory protein Ikk3 (or Nemo) (reviewed in ref. NF-κB, a major transcription factor for inflammatory responses, is found activated in Kras-transformed epithelial cells ( 7, 8).

#Taghon notched up a level full

Mouse models with pancreas-specific activation of oncogenic Kras display the full spectrum of PanINs and recapitulate the features of human PDAC ( 5, 6). Histological and molecular studies have demonstrated that disease progression occurs through a series of preinvasive lesions, pancreatic intraepithelial neoplasias (PanINs), that progress into invasive carcinoma ( 4). In contrast, inflammatory cytokines and signaling pathways affected by the genetic changes occurring in malignant diseases are attractive druggable targets.Īctivating mutations of the KRAS proto-oncogene are found in more than 90% of pancreatic ductal adenocarcinomas (PDACs), the most prevalent form of pancreatic cancer ( 3). Oncogenes and tumor suppressor genes are, however, difficult molecular targets in cancer therapy ( 2). Activation of proto-oncogenes such as ras and/or inactivation of tumor suppressors orchestrates a proinflammatory transcriptional program and constitutive production of inflammatory cytokines and chemokines that shape a tumor-promoting microenvironment. Most solid tumors are characterized by an intrinsic tumor-promoting inflammatory response ( 1). 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.Ĭancer-related inflammation has been shown to be critically linked with malignant disease - either by being the initiating, extrinsic cause or by supporting the intrinsic microenvironment during tumor progression ( 1). Thus, crosstalk between Tnf-α/Ikk2 and Notch sustains the intrinsic inflammatory profile of transformed cells. Hes1 suppresses expression of Pparg, which encodes the antiinflammatory nuclear receptor Pparγ.

Mechanistically, Tnf-α stimulation resulted in phosphorylation of histone H3 at the Hes1 promoter, and this signal was lost with Ikk2 deletion. Tnf-α stimulated canonical NF-κB signaling and, in collaboration with basal Notch signals, induced optimal expression of Notch targets. We found that in the Kras G12DPdx1-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. 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. These mutations result in increased activity of the NF-κB pathway and the subsequent constitutive production of proinflammatory cytokines. The majority of human pancreatic cancers have activating mutations in the KRAS proto-oncogene.