Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis
RNA Therapeutics Institute; Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology; Li Weibo Institute for Rare Diseases Research
Biochemistry | Cancer Biology | Enzymes and Coenzymes | Molecular Biology | Neoplasms
Colon cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, emphasizing the need for the discovery of new cellular targets. Using a metabolomics approach, we report here that epoxygenated fatty acids (EpFA), which are eicosanoid metabolites produced by cytochrome P450 (CYP) monooxygenases, were increased in both the plasma and colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer mice. CYP monooxygenases were overexpressed in colon tumor tissues and colon cancer cells. Pharmacologic inhibition or genetic ablation of CYP monooxygenases suppressed AOM/DSS-induced colon tumorigenesis in vivo. In addition, treatment with 12,13-epoxyoctadecenoic acid (EpOME), which is a metabolite of CYP monooxygenase produced from linoleic acid, increased cytokine production and JNK phosphorylation in vitro and exacerbated AOM/DSS-induced colon tumorigenesis in vivo. Together, these results demonstrate that the previously unappreciated CYP monooxygenase pathway is upregulated in colon cancer, contributes to its pathogenesis, and could be therapeutically explored for preventing or treating colon cancer. SIGNIFICANCE: This study finds that the previously unappreciated CYP monooxygenase eicosanoid pathway is deregulated in colon cancer and contributes to colon tumorigenesis.
DOI of Published Version
Cancer Res. 2019 Apr 15;79(8):1822-1830. doi: 10.1158/0008-5472.CAN-18-3221. Epub 2019 Feb 25. Link to article on publisher's site
Wang W, Yang J, Edin ML, Wang Y, Luo Y, Wan D, Yang H, Song C, Xue W, Sanidad KZ, Song M, Bisbee HA, Bradbury JA, Nan G, Zhang J, Shih PB, Lee KS, Minter LM, Kim D, Xiao H, Liu J, Hammock BD, Zeldin DC, Zhang G. (2019). Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis. Program in Molecular Medicine Publications. https://doi.org/10.1158/0008-5472.CAN-18-3221. Retrieved from https://escholarship.umassmed.edu/pmm_pp/95