title: Endogenous n-3 polyunsaturated fatty acids delay progression of pancreatic ductal adenocarcinoma in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice.
abstract: Preclinical studies suggest that diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be beneficial for prevention of pancreatic cancer. Nutritional intervention studies are often complex, and there is no clear evidence, without potential confounding factors, on whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection. Experiments were designed using n-3 fatty acid desaturase (Fat-1) transgenic mice, which can convert n-6 PUFA to n-3 FAs endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC). Six-week-old female p48(Cre/+)-LSL-Kras(G12D/+) and compound Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice were fed (AIN-76A) diets containing 10% safflower oil for 35 weeks. Pancreata were evaluated histopathologically for PanINs and PDAC. Results showed a dramatic reduction in incidence of PDAC (84%; P < .02) in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice compared to p48(Cre/+)-LSL-Kras(G12D/+) mice. Importantly, significant reductions of pancreatic ducts with carcinoma (90%; P < .0001) and PanIN 3 (~50%; P < .001) lesions were observed in the compound transgenic mice. The levels of n-3 PUFA were much higher (>85%; P < .05-0.01) in pancreas of compound transgenic mice than in those of p48(Cre/+)-LSL-Kras(G12D/+) mice. Molecular analysis of the pancreas showed a significant down-regulation of proliferating cell nuclear antigen, cyclooxygenase-2, 5-lipoxygenase (5-LOX), 5-LOX-activating protein, Bcl-2, and cyclin D1 expression levels in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice compared to p48(Cre/+)-LSL-Kras(G12D/+) mice. These data highlight the promise of dietary n-3 FAs for chemoprevention of pancreatic cancer in high-risk individuals.
authors: Center for Cancer Prevention and Drug Development, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors: Altaf
authors: A
authors: Mohammed
authors: Naveena B
authors: NB
authors: Janakiram
authors: Misty
authors: M
authors: Brewer
authors: Ashley
authors: A
authors: Duff
authors: Stan
authors: S
authors: Lightfoot
authors: Richard S
authors: RS
authors: Brush
authors: Robert E
authors: RE
authors: Anderson
authors: Chinthalapally V
authors: CV
authors: Rao
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D044943:Fatty Acid Desaturases / Q000235:genetics; D015525:Fatty Acids, Omega-3 / Q000235:genetics* / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D010183:Pancreatic Ducts / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D019938:Cyclin D1; D001094:Arachidonate 5-Lipoxygenase; D044943:Fatty Acid Desaturases; D051546:Cyclooxygenase 2