Release of arachidonic acid from membrane phospholipids by phospholipase A2 (PLA2) is the rate limiting event in the biosynthesis of a host of bioactive and mitogenic eicosanoids. Evidence indicates that eicosanoids are involved in the growth of both normal and transformed cells and significantly, inhibition of eicosanoid production prevents and reverses polyp formation associated with early progression of colon cancer. Small cell lung carcinoma (SCLC) growth is driven by autocrine loops involving secreted neuropeptides that signal though specific G protein-coupled receptors expressed on the tumor cells. Our preliminary data demonstrate that neuropeptides stimulate arachidonic acid release in SCLC through the activation of PLA2 and that blockers of eicostanoid production inhibit the growth of these cells. Non-small cell lung cancer (NSCLC), in contrast to SCLC, is associated with overactivity of the ECF receptor tyrosine kinase and activating mutations in the ras protooncogenes. Activation of receptor tyrosine kinase and activating mutations in the ras protooncogenes. Activation of receptor tyrosine kinases stimulates arachidonic acid release in a variety of cell types and studies report elevated prostaglandin production in NSCLC. Thus, PLA2 activation and arachidonic acid metabolism represents a potential convergence point in mitogenic signaling in diverse forms of lung cancer. We hypothesize that specific eicosanoids contribute to lung cancer progression and transformed growth of both SCLC and NSCLC. Furthermore, we anticipate that distinct patterns of arachidonic acid metabolites will be characteristic SCLC and NSCLC. To test this hypothesis, we will; 1. Identify specific arachidonic acid metabolites produced by SCLC and NSCLC cell lines. In addition, the expression of specific cyclooxygenase and lipoxygenase isoforms will be assessed using RT-PCR and immunoblotting strategies. 2. Define the mitogenic effects of arachidonic acid metabolites identified in Specific Aim I on lung cancer cells and examine their ability to regulate well-described mitogenic signalling pathways. 3. Determine the influence of known inhibitor of PLA2 and arachidonic acid metabolizing enzymes on the in vitro and in vivo growth properties of SCLC and NSCLC. Our goal is to define the role of arachidonic acid metabolism in the progression and transformed growth of lung cancer. The pharmaceutical industry has developed a large panel of drugs that selectively inhibit the various pathways of arachidonic acid release and metabolism. We anticipate that these agents in conjunction with existing therapies will translate to more effective treatment of lung cancer. In addition to production by advanced lung carcinomas, eicosanoids may play significant roles in the progression of lung cancer similar to their emerging role in colon cancer progression. Thus, inhibitors of eicosanoid production may also have significant chemopreventative properties for the control of early lung dysplasias.
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