KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

Abstract

SUMMARY Constitutive Kras and NF-κB activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-κB is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/β inactivation inhibited NF-κB activation and PDAC development in KrasG12D and KrasG12D;Ink4a/ArfF/F mice, demonstrating a mechanistic link between IKK2/β and KrasG12D in PDAC inception. Our findings reveal that KrasG12D-activated AP-1 induces IL-1α, which, in turn, activates NF-κB and its target genes IL-1α and p62, to initiate IL-1α/p62 feedforward loops for inducing and sustaining NF-κB activity. Furthermore, IL-1α overexpression correlates with Kras mutation, NF-κB activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/β/NF-κB is activated by KrasG12D through dual feedforward loops of IL-1α/p62.

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

“…1,3,4,47 This suggests that NF-kB-mediated p62/SQSTM1 upregulation may represent a feed-forward signal for prolongation of NF-kB activity and thus cell survival during granulocytic maturation. In line with this assumption, Ling et al 51 showed that the NF-kB pathway is activated by Kras (G12D) in pancreatic ductal adenocarcinoma through p62/SQSTM1 and IL-1 alpha feed-forward loops. In fact, the mutual regulation between p62/SQSTM1 and NF-kB pathways warrants further investigation.…”

Transient Aggregation of Ubiquitinated Proteins Is a Cytosolic Unfolded Protein Response to Inflammation and Endoplasmic Reticulum Stress

“…3B). During writing up of this study, Ling et al reported that IKK␤ activation is required for p62 expression during the development of pancreatic ductal adenocarcinoma (29). Further, there was attenuated mTOR activation caused by p50 deficiency.…”

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

“…[44][45][46][47][48] IL-1 has already been described to induce CCL22 expression. 6 Our data suggest a novel role of tumor cell-derived IL-1a, mediating CCL22 induction in immune cells and thus fostering the formation of an immunosuppressive micromilieu.…”