期刊
CANCER RESEARCH
卷 79, 期 8, 页码 1822-1830出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-3221
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资金
- University of Massachusetts Amherst
- USDA NIFA [2016-67017-24423]
- NIH/NCI [R03 CA218520]
- NIH/NIEHS [R01 ES002710, P42 ES004699, R00 ES024806]
- Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034]
- National Natural Science Foundation of China (NSFC) [81702832, 81470588]
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.
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