Elevation of n-3/n-6 PUFAs ratio suppresses mTORC1 and prevents colorectal carcinogenesis associated with APC mutation

Abstract

Although epidemiological and preclinical studies have shown the preventative effect of n-3 polyunsaturated fatty acids (PUFAs) on colorectal cancer (CRC), the underlying molecular mechanisms are not clear. In this study, we revealed that elevation of n−3/n-6 PUFAs ratio suppress the mechanistic target of rapamycin complex 1 (mTORC1) and prevent colorectal tumorigenesis. The transgenic expression of fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously, repressed colorectal tumor cell growth and remarkably reduced tumor burden, and alleviated anemia as well as hyperlipidemia in APC^Min/+ (adenomatous polyposis coli) mice, a classic CRC model that best simulates most clinical cases. In contrast to arachidonic acid (AA, C20:4 n−6), either Docosahexaenoic acid (DHA, C22:6 n−3), eicosapentaenoic acid (EPA, C20:5 n−3), or a combination of DHA and AA, efficiently inhibited the proliferation of CRC cell lines and promoted apoptosis in these cells. The ectopic expression of fat-1 had similar effects in colon epithelial cells with APC depletion. Mechanistically, elevation of n−3/n−6 ratio suppressed mTORC1 activity in tumors of APC^Min/+ mice, CRC cell lines with APC mutation, and in normal colon epithelial cells with APC depletion. In addition, elevation of n−3/n−6 ratio repressed mTORC1 activity and inhibited adipogenic differentiation in preadipocytes with APC knockdown, as well as alleviated hyperlipidemia in APC^Min/+ mice. Taken together, our findings have provided novel insights into the potential mechanism by which increase in n−3/n−6 PUFAs ratio represses CRC development, and also a new rationale for utilizing n-3 PUFAs in CRC prevention and treatment.