GROWTH-CONTROL OF LUNG-CANCER BY INTERRUPTION OF 5-LIPOXYGENASE-MEDIATED GROWTH-FACTOR SIGNALING

Signal transduction pathways shared by different autocrine growth fact ors may provide an efficient approach to accomplish clinically signifi cant control of lung cancer growth. In this study, we demonstrate that two autocrine growth factors activate 5-lipoxygenase action of the ar achidonic acid metabolic pathway in lung cancer cell lines. Both growt h factors increased the production of 5(S)-hydrooxyeicosa-6E,8Z,11Z,14 Z-tetraenoic acid (5-HETE), a major early 5-lipoxygenase metabolic pro duct. Exogenously added 5-HETE stimulated lung cancer cell growth in v itro. Inhibition of 5-lipoxygenase metabolism by selective antagonists resulted in significant growth reduction for a number of lung cancer cell lines. Primary clinical specimens and lung cancer cell lines expr ess the message for the 5-lipoxygenase enzymes responsible for the gen eration of active metabolites. In vivo evaluation demonstrated that in terruption of 5-lipoxygenase signaling resulted in enhanced levels of programmed cell death. These findings demonstrate that 5-lipoxygenase activation is involved with growth factor-mediated growth stimulation for lung cancer cell lines. Pharmacological intervention with lipoxyge nase inhibitors may be an important new clinical strategy to regulate growth factor-dependent stages of lung carcinogenesis.