Abstract 190: Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice by suppressing aldo-keto reductase family 1B10 (AKR1B10).

Abstract

Abstract Sulindac inhibits carcinogenesis via the mechanism that appears beyond cyclooxygenase inhibition. Recently sulindac has been identified as competitive inhibitors of aldo-keto reductase family 1B10 (AKR1B10). AKR1B10 is involved in the process of carbonyls, farnesyl and geranylgeranyl as well as retinal metabolisms, and these metabolic activities are important to carcinogenesis. However, there is no evidence on if inhibition of pancreatic carcinogenesis by sulindac is via inhibition of AKR1B10 and protein prenylation (i.e., Kras protein). To determine the effect of sulindac on pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice, five-week-old mice were fed with either AIN-93M diet or AIN-93M diet contained 200ppm sulindac (n=20 mice/group). Kaplan-Meier survival analysis with Log-Rank test was performed to analyze the effect of sulindac on animal survival from the development of pancreatic carcinoma. The results showed that average animal survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice was 143.7 ± 8.8 days; and with the sulindac 200ppm treatment, animal survival significantly increased to 168.0 ± 8.8 days (p<0.005). Extensively histopathological analyses revealed that 90% of mice developed malignant pancreatic carcinomas, of which 10% invasive pancreatic adenocarcinoma had metastasis to liver and lymph nodes. With 200ppm sulindac treatment, incidence of pancreatic cancer and its metastasis were significantly reduced to 56% and 0%, respectively (P<0.01). Immunchemical analysis showed that sulindac treatment significantly decreased Ki-67-labeled cell proliferation, increased caspase-3-labeled cell apoptosis, and suppressed phosphorylated ERK1/2. In vitro mouse pancreatic carcinoma cells derived from the LSL-KrasG12D/+-LSL-Trp53R172/+-Pdx-1-Cre mice were further treated with sulindac and revealed that sulindac inhibited AKR1B10 enzyme activity, suppressed Kras and HDJ2 protein prenylation, and further inhibited phosphylation of C-raf, ERK1/2 and MEK1/2. Similar to sulindac treatment, siRNA-silencing AKR1B10 expression resulted in a significant reduction of Kras protein prenylation and its downstream signals. Our results demonstrate that sulindac inhibits pancreatic carcinogenesis, mainly via inhibition of kras protein prenylation and its activated signals by targeting AKR1B10. (supported NCI R01 CA164041) Citation Format: Jie Liao, Yeon Tae Chung, Haonan Li, Wanying Zhang, Guang-Yu Yang. Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice by suppressing aldo-keto reductase family 1B10 (AKR1B10). [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 190. doi:10.1158/1538-7445.AM2013-190