INHIBITION OF ARACHIDONATE 5-LIPOXYGENASE TRIGGERS MASSIVE APOPTOSIS IN HUMAN PROSTATE-CANCER CELLS

Diets high in fat are associated with an increased risk of prostate ca ncer, although the molecular mechanism is still unknown, We have previ ously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells th rough production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyei cosatetraenoic acid). We now show that 5-HETE is also a potent surviva l factor for human prostate cancer cells. These cells constitutively p roduce 5-HETE in serum-free medium with no added stimulus. Exogenous a rachidonate markedly increases the production of 5-HETE, Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induc es massive apoptosis in both hormone-responsive (LNCaP) and -nonrespon sive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MKS86 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 a ntioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survi val factor for prostate cancer cells. Apoptosis was specific for 5-lip oxygenase-programmed cell death was not observed with inhibitors of 12 -lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachido nic acid metabolism, Exogenous 5-HETE protects these cells from apopto sis induced by 5-lipoxygenase inhibitors, confirming a critical role o f 5-lipoxygenase activity in the survival of these cells. These findin gs provide a possible molecular mechanism by which dietary fat may inf luence the progression of prostate cancer.