Abstract LB-299: Enhanced inhibitory effects on mutant KrasG12D-initiated murine pancreatic carcinoma growth in Fat-1 transgenic mice treated with soluble epoxide hydrolase inhibitor t-AUCB
Authors: Liao Jie , Xia Rong , Yang Jun , Li Haonan , Xu Dandan , Wang Xueyan , You Xiaoming , Hwang Sung Hee , Hammock Bruce , Yang Guang-Yu 
Published: July 2016

Anti-carcinogenic effects of ω-3 polyunsaturated fatty acid (PUFAs) are well known; but the mechanism/s remains unclear. Of the three metabolic pathways (COX, LOX, and CYP), ω-3 PUFAs are predominantly metabolized by cyto-p450 epoxygenase/s, leading to an accumulation of ω-3 epoxy fatty acid (ω-3 epoxides), and ω-3 PUFAs are poor substrates of COX and LOX. Functional studies indicate that ω-3 epoxides are highly potential metabolites responsible for anti-inflammatory/carcinogenic actions. However, under physiologic conditions, these ω-3 epoxides are quickly inactivated by soluble epoxide hydrolase (sEH) to the diol products, and a sEH inhibitor appears crucial to stabilizing/enhancing the actions of these ω-3 epoxides. Fat1 transgenic mouse constitutively converts ω-6 to ω-3 PUFAs in all organs and are an efficient model to study ω-3 PUFAs. Herein, we have determined if a potent sEH inhibitor t-AUCB enhanced the inhibitory effect on mutant KrasG12D-initiated pancreatic cancer growth in Fat-1 mice and further determined the metabolic profile of ω-3 PUFAs, particularly on epoxide metabolites. Using an implanted mouse pancreatic carcinoma model (PK03 cell line, obtained from LSL-KrasG12D/Pdx1-Cre mice), a significant reduction of in vivo implanted PK03 pancreatic carcinoma growth was observed in Fat1 mice compared to wild type mice (Tumor volume: 355 ± 50 vs 519 ± 61 mm3, P&lt;0.05), and with t-AUCB treatment the most significant reduction of tumor volume was observed (Tumor volume: 279 ± 35 vs 519 ± 61 mm3, P&lt;0.01), but no difference for tumor volume in wild type mice with or without t-AUCB treatment (522 ± 70 vs 519 ± 61 mm3). Using LC-MS/MS metabolomics approach, modulation of the full oxylipin profile, particularly increased ratio of epoxide metabolites/its corresponded diols for ω-3 PUFAs, was observed in Fat1 mice treated with t-AUCB. Western blot and immunohistochemistry analysis revealed a significant down-regulation of Kras-activated phosphorylated-form C-Raf, MEK and Erk, as well as an up-regulation of E-cadherin; and immunohistochemistry study further demonstrated that ki-67 labeled cell proliferation and myeloperoxidase-labeled inflammatory cells (neutrophils/macrophages) were significantly reduced and Caspase-3 labeled cell apoptosis was significantly increased in pancreatic carcinoma in Fat-1 mice treated with t-AUCB. These results indicate that sEH inhibitor t-AUCB combined with ω-3 PUFAs is a highly potential and efficient approach to treat and prevent pancreatic cancer, particularly via stabilizing ω-3 epoxides. (Supported by NIH R01CA164041 and R01CA172431)

Citation Format: Jie Liao, Rong Xia, Jun Yang, Haonan Li, Dandan Xu, Xueyan Wang, Xiaoming You, Sung Hee Hwang, Bruce Hammock, Guang-Yu Yang. Enhanced inhibitory effects on mutant KrasG12D-initiated murine pancreatic carcinoma growth in Fat-1 transgenic mice treated with soluble epoxide hydrolase inhibitor t-AUCB. [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 LB-299.