title: 15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival.
abstract: A 15-LOX, it is proposed, suppresses the growth of prostate cancer in part by converting arachidonic, eicosatrienoic, and/or eicosapentaenoic acids to n-6 hydroxy metabolites. These metabolites inhibit the proliferation of PC3, LNCaP, and DU145 prostate cancer cells but only at ≥1-10 µM. We show here that the 15-LOX metabolites of docosahexaenoic acid (DHA), 17-hydroperoxy-, 17-hydroxy-, 10,17-dihydroxy-, and 7,17-dihydroxy-DHA inhibit the proliferation of these cells at ≥0.001, 0.01, 1, and 1 µM, respectively. By comparison, the corresponding 15-hydroperoxy, 15-hydroxy, 8,15-dihydroxy, and 5,15-dihydroxy metabolites of arachidonic acid as well as DHA itself require ≥10-100 µM to do this. Like DHA, the DHA metabolites a) induce PC3 cells to activate a peroxisome proliferator-activated receptor-γ (PPARγ) reporter, express syndecan-1, and become apoptotic and b) are blocked from slowing cell proliferation by pharmacological inhibition or knockdown of PPARγ or syndecan-1. The DHA metabolites thus slow prostate cancer cell proliferation by engaging the PPARγ/syndecan-1 pathway of apoptosis and thereby may contribute to the prostate cancer-suppressing effects of not only 15-LOX but also dietary DHA.
authors.affiliation: Department of Internal Medicine Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: O'Flaherty
authors.forename: Yungping
authors.initials: Y
authors.lastname: Hu
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Wooten
authors.forename: David A
authors.initials: DA
authors.lastname: Horita
authors.forename: Michael P
authors.initials: MP
authors.lastname: Samuel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.forename: Haiguo
authors.initials: H
authors.lastname: Sun
authors.forename: Iris J
authors.initials: IJ
authors.lastname: Edwards
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D053668:Syndecan-1; D004281:Docosahexaenoic Acids; D001093:Arachidonate 15-Lipoxygenase; D020169:Caspases