RESUMEN
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplements have exhibited inconsistent effects on cancer risk, and their potential efficacy as cancer preventive agents has been increasingly questioned, especially in recent large randomized clinical trials. The role of host factors that govern EPA and DHA metabolism in relation to their impact on carcinogenesis remains understudied. Resolvins, the products of EPA and DHA oxidative metabolism, demonstrate intriguing antitumorigenic effects through mechanisms such as promoting macrophage phagocytosis of cell debris and inhibiting the production of proinflammatory chemokines and cytokines by tumor-associated macrophages (TAMs), which are crucial for cancer progression. However, clinical studies have not yet shown a significant increase in target tissue levels of resolvins with EPA and DHA supplementation. 15-Lipoxygenase-1 (ALOX15), a key enzyme in EPA and DHA oxidative metabolism, is often lost in various major human cancers, including precancerous and advanced colorectal cancers. Further research is needed to elucidate whether the loss of ALOX15 expression in colorectal precancerous and cancerous cells affects EPA and DHA oxidative metabolism, the formation of resolvins, and subsequently carcinogenesis. The findings from these studies could aid in the development of novel and effective chemoprevention interventions to reduce cancer risk.
RESUMEN
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids (ω-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1ß, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC. Significance: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1ß, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.