Oncotarget

Research Papers:

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

Miao Liu, Ling Zhou, Baiyu Zhang, Minhong He, Xiaoying Dong, Xiaojun Lin, Chunhong Jia, Xiaochun Bai, Yifan Dai, Yongchun Su, Zhipeng Zou and Hang Zheng _

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Oncotarget. 2016; 7:76944-76954. https://doi.org/10.18632/oncotarget.12759

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Abstract

Miao Liu1,*, Ling Zhou1,*, Baiyu Zhang2, Minhong He1, Xiaoying Dong1, Xiaojun Lin3, Chunhong Jia3, Xiaochun Bai3, Yifan Dai4, Yongchun Su5, Zhipeng Zou3, Hang Zheng1

1Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

2Department of Rheumatology, the Sixth Affiliated Hospital of Sun Yat-Sen University, 510655, China

3Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China

4State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 201129, China

5Department 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: [email protected]

Zhipeng Zou, email: [email protected]

Hang Zheng, email: [email protected]

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 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.


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