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// Miao Liu 1, * , Ling Zhou 1, * , Baiyu Zhang 2 , Minhong He 1 , Xiaoying Dong 1 , Xiaojun Lin 3 , Chunhong Jia 3 , Xiaochun Bai 3 , Yifan Dai 4 , Yongchun Su 5 , Zhipeng Zou 3 , Hang Zheng 1 1 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China 2 Department of Rheumatology, the Sixth Affiliated Hospital of Sun Yat-Sen University, 510655, China 3 Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China 4 State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 201129, China 5 Department of Bioinformatics, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China * These authors contributed equally to this work Correspondence to: Yongchun Su, email: suyc@smu.edu.cn Zhipeng Zou, email: zzp@smu.edu.cn Hang Zheng, email: zhengh001@163.com Keywords: PUFA, mTOR complex 1, colorectal cancer, APC Received: January 23, 2016 Accepted: October 10, 2016 Published: October 19, 2016 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. |