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.
Highlights
Colorectal cancer (CRC) ranks the second most prevalent cancer among women and the third among men worldwide [1]
To investigate the potential protective role of increasing n-3/n-6 ratio against colorectal cancer (CRC) associated with adenomatous polyposis coli (APC) mutation www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget in vitro, we examined the effect of Docosahexaenoic acid (DHA, C22:6 n−3), eicosapentaenoic acid (EPA, C20:5 n-3), arachidonic acid (AA, C20:4 n−6), or a combination of both DHA or AA, on the proliferation of SW480, a CRC cell line with truncated APC and with constitutively active β-catenin-TCF-regulated transcription (CRT, the best established hallmark of activated Wnt signaling), and on the proliferation of HCT116 cells, a CRC cell line with a β-catenin mutation that leads to constitutively active CRT [29]
Due to inconsistent results brought by the varieties of polyunsaturated fatty acids (PUFAs), we crossed fat-1 mice, which convert n−6 PUFAs to n−3 PUFAs endogenously, with APCMin/+ mice, generating a novel fat-1-APCMin/+ double transgenic mice model to study the effects of endogenous n−3 PUFAs on colorectal carcinogenesis associated with APC mutation
Summary
Colorectal cancer (CRC) ranks the second most prevalent cancer among women and the third among men worldwide [1]. Source, and ratio of PUFAs vary widely and lead to inconsistent results, a transgenic mouse model that expresses fat-1, an n−3 fatty acid desaturase, was developed [22]. Since this enzyme can catalyze the conversion of n-6 PUFAs to n−3 PUFAs by introducing a double bond into fatty acyl chains, the fat-1 transgenic mice will enable the investigation of the biological properties of n-3 PUFAs without having to incorporate n−3 PUFAs in the diet, and this strategy represents a more reliable and intuitive model [23]. For the first time we crossed fat-1 transgenic mice with APCMin/+ mice and generated a novel mouse strain, fat-1-APCMin/+ double-hybrid, to investigate the preventive effects of elevation of n–3/n–6 ratio on CRC associated with APC mutation and the underlying mechanisms. Our results provide a new rationale and exciting therapeutic value of utilizing n–3 PUFAs to target CRC and associated anemia, in cases involving APC mutation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
