Abstract 665: Blocking IL-1-NF-kB axis inhibits Kras-induced pancreatic ductal adenocarcinoma

Autor: Yu Cao, Jie Fu, Paul J. Chiao, Min Wu, Jianhua Ling
Rok vydání: 2016
Předmět:
Zdroj: Cancer Research. 76:665-665
ISSN: 1538-7445
0008-5472
Popis: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the USA with approximately 50 000 new cases and 40 000 deaths in 2015.The 5-year survival rate has remained at 5% for the past three decades and the median survival duration is less than 6 months. The very high rate of mutant Kras occurs in pancreatic cancer (>90%) and pancreatic intraepithelial neoplasia (panIN) (>50%). However, the key signaling pathway of downstream Kras remains unidentified. We previously uncovered that the NF-êB signaling pathway was constitutively activated in most PDAC specimens and pancreatic cancer cell lines. More recently, our results showed that constitutive NF-êB activity in PDAC was induce by IL-1 autocrine mechanism. IL-1/p62 feedforward loops that initiated by the mutant Kras sustained NF-êB activity and were required for pancreatic cancer development. Therefore, we hypothesize that blocking IL-1 - NF-êB signaling pathway will inhibit Kras-induced pancreatic ductal adenocarcinoma. To identify the mechanistic role of mutant Kras-induced IL-1 expression in PDAC, we generated genetically engineered mice of Pdx1-cre/Kras LSL-G12D/p53 M/+IL-1á−/−. Our findings revealed that these mutant mice had developed significantly less PDAC number and a significantly delayed PDAC at old ages. Furthermore, we assess the effect of pharmacological IL-1R1 antagonist (anakinra) in human pancreatic cancer cell lines and orthotopic pancreatic cancer mouse. We found that IL-1R1 antagonist significantly decreased NF-êB activity and inhibited cell proliferation, migration and invasion. More interestingly, the combinational treatment IL-1R1 antagonist plus gemcitabine significantly reduced the tumor burden in orthotopic pancreatic cancer mouse. These results suggested that pharmacologically targeting IL-1á may provide a novel therapeutic approach for pancreatic cacner. Citation Format: Jianhua Ling, Jie Fu, Min Wu, Yu Cao, Paul Chiao. Blocking IL-1-NF-kB axis inhibits Kras-induced pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 665.
Databáze: OpenAIRE
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