Abstract 3702: Aldo-keto reductase family 1B10 (AKR1B10) knockdown or inhibition suppresses pancreatic tumorigenesis in vitro and in vivo.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC AKR1B10 is a member of aldo-keto reductase family and has relatively specific lipid substrates including carbonyls, retinal and farnesal/geranylgeranial. Metabolizing these substracts is crucial in carcinogenesis, particularly for the reduction of farnesal/geranylgeranial to farnesol/ geranylgeraniol that is an important step for recycling the intermediates of cholesterol synthesis and for protein prenylation. Mutant KRAS is a most common oncogene involved in the development of pancreatic cancer, and KRAS requires protein prenylation for its activity. The aims of this study were to determine oncogenic role of AKR1B10 in pancreatic tumorigenesis. Using shRNA knockdown approach and AKR1B10 inhibitor oleanoic acid (OA) in CD18 human pancreatic carcinoma cells, silencing of AKR1B10 resulted in a significant inhibition of anchor-dependent growth (170±3.7colonies/HPF vs. 67±9.5colonies/HPF, P<0.01), and AKR1B10 inhibtor OA showed a dose-dependent inhibition of cell growth with IC50 of 30μM. Cell invasion study showed a significant decreased invasion index in shRNA AKR1B10 knockdown cells compared to vector-control cells (0.27 vs. 1.00). A significant inhibition of cell migration in shRNA AKR1B10 knockdown cells compared to vector control cells was observed and showed cell migration index14.0±1.8% vs. 9.2±1.2% at 16 hours, 30.5±3.5% vs. 21.0±1.1% at 24 hours, and 88.9±3.0% vs. 51.9±5.7% at 48 hours (P<0.01). AKR1B10 enzyme activity was also inhibited by OA as dose- dependent pattern. Western blot analysis revealed a significant down-regulation of active form KRAS and its downstream signals including phosphorylated C-Raf, ErK, and MEK1/2 as well as an up-regulation of E-cadherin. A significant reduction of in vivo tumor growth was observed in shRNA AKR1B10 knockdown CD18 pancreatic carcinoma cells implanted in nude mice as compared to vector-control CD18 human pancreatic carcinoma cells (tumor volume: 275.9±68.9mm3 vs. 582.7±10.5.6mm3, P=0.03; and tumor weight: 0.25±0.06g vs. 0.52±0.07g, P=0.01). Implanted CD18 pancreatic carcinomas in nude mice were further treated AKR1B10 inhibitor OA and showed a significant smaller tumor size (315.6±50.8mm3 vs. 582.7±10.5.6mm3, P=0.03) and tumor weight (0.35±0.05g vs. 0.52±0.07g, P=0.05) as compared to non OA treated tumor. With immunohistochemical approach, Ki67-labeled cell proliferation and phosphorylated ERK1/2 exhibited a significant lower in CD18 pancreatic carcinoma with either shRNA AKR1B10 knockdown or AKR1B10 inhibition. Our findings provide evidence that AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis and in modulation of protein prenylation (KRAS). Thus, AKR1B10 could be a potential target for prevention and treatment of highly lethal pancreatic carcinoma. (supported NCI R01 CA164041) Citation Format: Wanying Zhang, Haonan Li, Jie Liao, Guang-Yu Yang. Aldo-keto reductase family 1B10 (AKR1B10) knockdown or inhibition suppresses pancreatic tumorigenesis in vitro and in vivo. [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 3702. doi:10.1158/1538-7445.AM2013-3702