title: 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 APCMin/+ (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 APCMin/+ 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 APCMin/+ 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.
authors: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors: Miao
authors: M
authors: Liu
authors: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors: Ling
authors: L
authors: Zhou
authors: Department of Rheumatology, The Sixth Affiliated Hospital of Sun Yat-Sen University, 510655, China.
authors: Baiyu
authors: B
authors: Zhang
authors: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors: Minhong
authors: M
authors: He
authors: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors: Xiaoying
authors: X
authors: Dong
authors: Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors: Xiaojun
authors: X
authors: Lin
authors: Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors: Chunhong
authors: C
authors: Jia
authors: Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors: Xiaochun
authors: X
authors: Bai
authors: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 201129, China.
authors: Yifan
authors: Y
authors: Dai
authors: Department of Bioinformatics, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors: Yongchun
authors: Y
authors: Su
authors: Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors: Zhipeng
authors: Z
authors: Zou
authors: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors: Hang
authors: H
authors: Zheng
mesh_terms: D041721:3T3-L1 Cells; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000517:prevention & control*; D044943:Fatty Acid Desaturases / Q000235:genetics*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000494:pharmacology; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; C000613192:adenomatous polyposis coli protein, mouse; D044943:Fatty Acid Desaturases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: APC; PUFA; colorectal cancer; mTOR complex 1