Abstract 2741: NF-κB activation by IL-1α and p62 feedforward loops is required for Kras-induced pancreatic ductal adenocarcinoma.

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a less than six month mean survival period and less than five percent of an overall five-year survival rate. Despite developments in the management of pancreatic cancer, the survival rate has remained unchanged in the past 50 years. Thus, a better understanding of the mechanism of pancreatic cancer inception and development is the key to identifying prevention strategies and therapeutic targets for increasing patient survival rates, which is one of the greatest challenges in pancreatic cancer research. The mutational activation of Kras is an early event in PDAC development and has been detected in 90% of PDAC and 50% of pancreatic intraepithelial neoplasia (PanIN). The genetic mutation of oncogenic Kras in the pancreas induces chronic pancreatitis and pancreatic cancer. However, the key signaling pathway of the downstream Kras remains unidentified. Here, we report that pancreas-specific 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/NF-kB signaling pathway and KrasG12D signaling pathways 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. Knock-down of IL-1α in mouse PDAC cell lines and lung adenocarcinoma cell lines significantly reduces tumorigenesis in orthotopic xenograft mouse and subcutaneous xenograft mouse models. Therefore, our findings demonstrate the new mechanism by which IKK2/β/NF-κB is activated by KrasG12D through dual feedforward loops of IL-1α/p62 to promote development of PDAC. This suggests that the interruption of the dual feedforward loops of IL-1α/p62 could be the therapeutic targets for inhibiting oncogenic Kras signaling in PDAC. Citation Format: Jianhua Ling, Ya'an Kang, Paul Chiao. NF-κB activation by IL-1α and p62 feedforward loops is required for Kras-induced pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2013-2741