Prevention of diabetes-promoted colorectal cancer by (n-3) polyunsaturated fatty acids and (n-3) PUFA mimetic.
The global obesity / diabetes epidemic has resulted in robust increase in the incidence of colorectal cancer (CRC). Epidemiological, animal and human studies have indicated efficacy of (n-3) PUFA in chemoprevention of sporadic and genetic-driven CRC. However, diabetes-promoted CRC presents a treatment challenge that surpasses that of sporadic CRC. This report analyzes the efficacy of (n-3) PUFA generated by the fat-1 transgene that encodes an (n-6) to (n-3) PUFA desaturase, and of synthetic (n-3) PUFA mimetic (MEDICA analog), to suppress CRC development in carcinogen-induced diabetes-promoted animal model. Carcinogen-induced CRC is shown here to be promoted by the diabetes context, in terms of increased aberrant crypt foci (ACF) load, cell proliferation and epithelial dedifferentiation, being accompanied by increase in the expression of HNF4α, β-catenin, and β-catenin-responsive genes. Incorporating the fat-1 transgene in the diabetes context, or oral MEDICA treatment, resulted in ameliorating the diabetic phenotype and in abrogating CRC, with decrease in ACF load, cell proliferation and the expression of HNF-4α, β-catenin, and β-catenin-responsive genes. The specificity of (n-3) PUFA in abrogating CRC development, as contrasted with enhancing CRC by (n-6) PUFA, was similarly verified in CRC cell lines. These findings may indicate prospective therapeutic potential of (n-3) PUFA or MEDICA in the management of CRC, in particular diabetes-promoted CRC.
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
Anna
A
Algamas-Dimantov
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
Einav
E
Yehuda-Shnaidman
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
Rachel
R
Hertz
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
Irena
I
Peri
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel.
Jacob
J
Bar-Tana
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
Betty
B
Schwartz
D058739:Aberrant Crypt Foci / Q000473:pathology; D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology*; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D048909:Diabetes Complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D051176:beta Catenin / Q000096:biosynthesis
D005231:Fatty Acids, Unsaturated; D051557:Hepatocyte Nuclear Factor 4; D051176:beta Catenin