Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis
Authors
Wang, WeicangYang, Jun
Edin, Matthew L.
Wang, Yuxin
Luo, Ying
Wan, Debin
Yang, Haixia
Song, Chun-Qing
Xue, Wen
Sanidad, Katherine Z.
Song, Mingyue
Bisbee, Heather A.
Bradbury, Jennifer A.
Nan, Guanjun
Zhang, Jianan
Shih, Pei-An Betty
Lee, Kin Sing Stephen
Minter, Lisa M.
Kim, Daeyoung
Xiao, Hang
Liu, Jun-Yan
Hammock, Bruce D.
Zeldin, Darryl C.
Zhang, Guodong
UMass Chan Affiliations
Li Weibo Institute for Rare Diseases ResearchDepartment of Molecular, Cell and Cancer Biology
Program in Molecular Medicine
RNA Therapeutics Institute
Document Type
Journal ArticlePublication Date
2019-04-15
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1158/0008-5472.CAN-18-3221Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44499PubMed ID
30803995Related Resources
ae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-18-3221