Abstract A111: Endogenous conversion of n-6 PUFAs to n-3 PUFAs prevents progression of K-Ras activated pancreatic lesion development to pancreatic ductal carcinoma in Fat-1 transgenic mice

Abstract

Abstract Developing novel strategies to prevent or delay the progression of pancreatic ductal adenocarcinoma (PDAC), a devastating disease with a dismal 5-year survival rate (<5%), is of utmost importance. Preclinical studies suggest that omega-3 fatty acid (n-3 PUFA)-rich diets may be beneficial for pancreatic cancer prevention. Nutritional intervention studies are often complex and there is no clear evidence whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection without potential confounding factors of interference. Thus, experiments were designed using fat-1 transgenic (n-3 fatty acid desaturase) mice, which can convert n-6 PUFA to n-3 PUFA endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC. LSL-KrasG12D/+ and p48Cre/+ mice were bred with Fat-1 mice and offspring of activated p48Cre/+-LSL-KrasG12D/+ and Fat-1-p48Cre/+-LSL-KrasG12D/+ were generated. Six-week old transgenic mice p48Cre/+-LSL-KrasG12D/+ (12/group), Fat-1-p48Cre/+-LSL-KrasG12D/+ (12/group), and wild-type (12/group) mice were fed (AIN-76A) a diet containing 10% safflower oil for 35 weeks. Pancreata were collected, weighed, and evaluated histopathologically for PanINs and PDAC. To understand the mechanisms, we analyzed levels of fatty acids and assessed the proliferation, apoptosis, and cell cycle markers by GC, IHC, IHF, Western blotting, Real time and/or RT-PCR. Results show a dramatic reduction in incidence of PDAC (85.8% p<0.02) in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. Importantly, significant reduction of pancreatic ducts with carcinoma (90%, p< 0.0001) and a significant suppression of PanIN 3 (∼50%; p<0.001) were observed in Fat-1-p48Cre/+-LSL-KrasG12D/+ transgenic mice. The levels of n-3 PUFA, -Linoleic acid, DPA and DHA were much higher (∼90%) in pancreatic tissues of Fat-1-p48Cre/+-LSL-KrasG12D/+ mice than that of p48Cre/+-LSL-KrasG12D/+ and WT animals. Importantly, molecular analysis of pancreas showed a significant down-regulation of fatty acid synthase, insulin receptor, insulin receptor substrate-1, PCNA, COX-2, 5-LOX, FLAP, Bcl-2, and cyclin D1 expression levels in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+. These data highlight the potential for use of n-3 fatty acids for chemoprevention of pancreatic cancer and represent an important strategy to delay/prevent pancreatic cancer in high-risk individuals. {Supported by Kerley-Cade Chair Endowment for Cancer Research} Citation Information: Cancer Prev Res 2011;4(10 Suppl):A111.