Abstract 1258: Knockdown or inhibition of Aldo-keto reductase 1B10 inhibits pancreatic carcinogenesis via modulating Kras-E-cadherin pathway

Abstract

Abstract Aldo-keto reductase 1B10 (AKR1B10) is an essential enzyme in the metabolism of carbonyls, retinal and farnesal/geranylgeranial for maintaining cellular homeostasis of retinal-retinoid acid, detoxifying the active carbonyls, and recycling key intermediate products of cholesterol synthesis. All of these biologic processes are crucial contributing to carcinogenesis, particularly the reduction of farnesal/geranylgeranial involves in protein prenylation and for mutant K-ras activity. Mutant K-ras is a most common oncogene in pancreatic cancer, and over expression of AKR1B10 has been identified in pancreatic cancer. To determine the role of AKR1B10 in pancreatic carcinogenesis, silencing of AKR1B10 was achieved in CD18 human pancreatic carcinoma cell line using shRNA knockdown approach. Silencing of AKR1B10 resulted in a significant inhibition of anchor-dependent growth (shRNA AKR1B10 knockdown cells compared to vector-control cells 67 ± 9.5 colonies/HPF vs 170 ± 3.7 colonies/HPF, P < 0.01), invasion index (0.27 vs. 1.00, p<0.05), and cell migration (at 16 hours 9.2 ± 1.2% vs 14.0 ± 1.8%, at 24 hours 21.0 ± 1.1% vs 30.5 ± 3.5%, and at 48 hours 51.9 ± 5.7% vs 88.9 ± 3.0%, P < 0.01). Oleanolic acid (OA), a naturally occurring triterpenoid compound, showed a potent inhibition of AKR1B10 activity and a dose-dependent inhibition of cell growth with IC50 at 30µM. K-ras pull-down and Western blot analysis revealed a significant down-regulation of active form K-ras and phosphorylated C-Raf, and ErK,as well as an up-regulation of E-cadherin by either AKR1B10 knockdown or inhibition. A significant reduction of in vivo tumor growth was observed in nude mice implanted the CD18 pancreatic carcinoma cells with shRNA AKR1B10 knockdown (tumor weight: 0.25 ± 0.06g vs. 0.52 ± 0.07g, P = 0.01), and with AKR1B10 inhibitor OA (tumor weight: 0.35 ± 0.05g vs. 0.52 ± 0.07g, P = 0.05). Our findings indicate AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis possibly via modulation of protein prenylation (KRAS)-E-Cadherin pathway. (supported by NIH R01CA164041) Note: This abstract was not presented at the meeting. Citation Format: Wanying Zhang, Haonan Li, Ke Ma, Jie Liao, Guang-Yu Yang. Knockdown or inhibition of Aldo-keto reductase 1B10 inhibits pancreatic carcinogenesis via modulating Kras-E-cadherin pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1258. doi:10.1158/1538-7445.AM2014-1258