title: Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.
abstract: Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer.
authors.affiliation: University of Virginia Cancer Center, Charlottesville, VA 22908, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ghosh
authors.forename: C E
authors.initials: CE
authors.lastname: Myers
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004041:Dietary Fats; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000633:toxicity; D044950:Flavanones; D005419:Flavonoids / Q000633:toxicity; D006035:Glycyrrhiza; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D007052:Ibuprofen / Q000633:toxicity; D007211:Indoles / Q000633:toxicity; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D008954:Models, Biological; D009707:Nucleosomes / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress; D029596:Paeonia; D010539:Permeability; D010718:Phosphatidylserines / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D002722:Chlorobenzenes
chemical_list: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000970:Antineoplastic Agents; D004041:Dietary Fats; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D044950:Flavanones; D005419:Flavonoids; D006893:Hydroxyeicosatetraenoic Acids; D007052:Ibuprofen; D007211:Indoles; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D009707:Nucleosomes; D010718:Phosphatidylserines; C038462:shakuyaku-kanzoh-toh; C060893:MK-886; D002722:Chlorobenzenes; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C006680:baicalein