title: Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids.
abstract: Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis:ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) andct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET).ct-8,9-E-11-HET andct-8,9-E-15-HET are further metabolized by sEH, withct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed thatct-8,9-E-11-HET is proangiogenic, whereasct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifiesct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.
authors.affiliation: Department of Entomology and Nematology, University of California, Davis, CA 95616.|UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Amy A
authors.identifier: 0000-0003-4465-4930
authors.initials: AA
authors.lastname: Rand
authors.affiliation: Department of Entomology and Nematology, University of California, Davis, CA 95616.|UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Barnych
authors.affiliation: Department of Entomology and Nematology, University of California, Davis, CA 95616.|UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: West Coast Metabolomics Center, UC Davis Genome Center, University of California, Davis, CA 95616.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cajka
authors.affiliation: Department of Entomology and Nematology, University of California, Davis, CA 95616.|UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Kin Sing Stephen
authors.initials: KSS
authors.lastname: Lee
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.|Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.affiliation: Department of Entomology and Nematology, University of California, Davis, CA 95616; bdhammock@ucdavis.edu.|UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Bruce D
authors.identifier: 0000-0003-1408-8317
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006801:Humans
chemical_list: D043925:Angiogenesis Inducing Agents; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015126:8,11,14-Eicosatrienoic Acid
keywords: angiogenesis; cyclooxygenase; epoxyeicosatrienoic acids; metabolism; omega-6 fatty acids