Lipidomic Profiling Identifies Cytochrome P450 as A Therapeutic Target for Colitis‐Associated Colorectal Cancer

Abstract

Eicosanoids and associated lipid mediators play central roles in regulating inflammation and carcinogenesis. While most previous studies of lipid mediators in colorectal cancer have only analyzed single or limited number of lipid mediators, few systematic studies have been carried out. Here we used a LC‐MS/MS‐based lipidomics, which can analyze >100 bioactive lipid mediators produced by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, to profile azoxymethane (AOM)/dextran sulfate sodium (DSS)‐induced colorectal cancer in mice. Lipidomics showed that CYP‐derived fatty acid epoxides were the only lipid mediators which were increased in both plasma and colon tissues of AOM/DSS‐treated mice. RT‐PCR and western blotting validated that the expressions of CYP were increased, while the expression of soluble epoxide hydrolase (the dominant enzyme in degrading fatty acid epoxides) was reduced, in colon tissues of AOM/DSS‐treated mice. To study the functional roles of CYP enzymes, we treated mice with SKF‐525A and clotrimazole, which are two different selective inhibitors of CYP enzymes involved in biosynthesis of fatty acid epoxides, and found that CYP inhibitors significantly suppressed AOM/DSS‐induced colorectal cancer in mice. To elucidate the specific lipid mediator involved in the pro‐colorectal cancer effects of CYP, we treated mice with epoxyoctadecenoic acids (EpOMEs) which are metabolites of linoleic acid produced by CYP, and found that EpOMEs worsened DSS‐induced colitis. Together, these results suggest that the previously unappreciated CYP pathway plays critical roles in promoting progression of colorectal cancer through formation of pro‐inflammatory EpOMEs, and CYP enzymes could be novel therapeutic targets of colitis‐associated colorectal cancer.Support or Funding InformationUSDA NIFA 2016‐67017‐24423, NIEHS R01 ES002710 and Superfund Research Program P42 ES04699