Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions

Many arachidonic acid metabolites function in growth signaling for epitheli al cells, and we previously reported the expression of the major arachidoni c acid enzymes in human breast cancer cell lines. To evaluate the role of t he 5-lipoxygenase (5-LO) pathway on breast cancer growth regulation, we exp osed cells to insulinlike growth factor-1 or transferrin, which increased t he levels of the 5-LO metabolite, 5(S)-hydrooxyeicosa-6E,8C,11Z,14Z-tetraen oic acid (5-HETE), by radioimmunoassay and high-performance liquid chromato graphy. Addition of 5-HETE to breast cancer cells resulted in growth stimul ation, whereas selective biochemical inhibitors of 5-LO reduced the levels of 5-HETE and related metabolites. Application of 5-LO or 5-LO activating p rotein-directed inhibitors, but not a cyclooxygenase inhibitor, reduced gro wth, increased apoptosis, down-regulated bcl-2, up-regulated bax, and incre ased G1 arrest. Exposure of breast cancer cells to a 5-LO inhibitor up-regu lated peroxisome proliferator-activated receptor (PPAR)alpha and PPAR gamma expression, and these same cells were growth inhibited when exposed to rel evant PPAR agonists. These results suggest that disruption of the 5-LO sign aling pathway mediates growth arrest and apoptosis in breast cancer cells. Additional experiments suggest that this involves the interplay of several factors, including the loss of growth stimulation by 5-LO products, the ind uction of PPAR gamma, and the potential activation of PPAR gamma by interac tions with shunted endoperoxides.