ω-3 Polyunsaturated fatty acids and their cytochrome P450-derived metabolites suppress colorectal tumor development in mice

Abstract

Many studies have shown that dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) reduces the risks of colorectal cancer; however, the underlying mechanisms are not well understood. Here we used a LC-MS/MS-based lipidomics to explore the role of eicosanoid signaling in the anti-colorectal cancer effects of ω-3 PUFAs. Our results showed that dietary feeding of ω-3 PUFAs-rich diets suppressed growth of MC38 colorectal tumor, and modulated profiles of fatty acids and eicosanoid metabolites in C57BL/6 mice. Notably, we found that dietary feeding of ω-3 PUFAs significantly increased levels of epoxydocosapentaenoic acids (EDPs, metabolites of ω-3 PUFA produced by cytochrome P450 enzymes) in plasma and tumor tissue of the treated mice. We further showed that systematic treatment with EDPs (dose=0.5 mg/kg per day) suppressed MC38 tumor growth in mice, with reduced expressions of pro-oncogenic genes such as C-myc, Axin2, and C-jun in tumor tissues. Together, these results support that formation of EDPs might contribute to the anti-colorectal cancer effects of ω-3 PUFAs.

Keywords: Colorectal cancer; Docosahexaenoic acid (DHA); Epoxydocosapentaenoic acids (EDPs); Lipidomics; ω-3 Polyunsaturated fatty acids (PUFAs).

Fig. 1.

Dietary feeding of ω-3 PUFAs-rich diets suppressed growth of MC38 colorectal tumor in mice. (A) scheme of animal experiment, (B) time-course of MC38 tumor sizing, (C) quantification of tumor weight, (D) representative image of dissected MC38 tumors, (E) flow cytometry quantification of endothelial cells in MC38 tumors. n = 8 mice per group, the results are expressed as mean ± SEM, * P < 0.05.

Fig. 2.

Dietary feeding of ω-3 PUFAs-rich diets modulated profiles of eicosanoid metabolites from CYP pathway in mice. (A) scheme of CYP pathway. (B) plasma, (C) MC38 tumor, and (D) colon profiles of CYP-derived fatty acid epoxide and diols. n = 4 mice per group for control and DHA-high groups, n = 3 mice per group for DHA group, the results are expressed as mean ± SEM, * P < 0.05.

Fig. 3.

Dietary feeding of ω-3 PUFAs-rich diets modulated profiles of eicosanoid metabolites from COX and LOX pathway in mice. (A) plasma, (B) MC38 tumor, and (C) colon profiles of COX-derived prostaglandins and thromboxanes. (B) plasma, (C) MC38 tumor, and (D) colon profiles of LOX-derived metabolites. n = 4 mice per group for control and DHA-high groups, n = 3 mice per group for DHA group, the results are expressed as mean ± SEM, * P < 0.05.

Fig. 4.

Treatment with synthetic EDPs suppressed growth of MC38 tumor in C57BL/6 mice. (A) time-course of MC38 tumor sizing, (B) representative images of dissected MC38 tumors, and quantification of tumor weight, (C) flow cytometry analysis of immune cells in MC38 colon tumors, and (D) RT-PCR analysis of pro-oncogenic genes in MC38 tumors. n = 9–10 mice per group, the results are expressed as mean ± SEM, * P < 0.05.