INDUCTION OF CYTOSOLIC PHOSPHOLIPASE A(2) BY ONCOGENIC RAS IN HUMAN NONSMALL CELL LUNG-CANCER

Mutations in Ras family members that confer oncogenic potential are fr equently observed in specific human cancers. We report that human non- small cell lung cancer (NSCLC) lines that harbor oncogenic mutations i n Ki-Ras (H460, A549, H2122) synthesized high levels of prostaglandin E-2 (PGE(2)) compared with NSCLC lacking Ras mutations or non-transfor med lung epithelial cells (BEAS-2B). This increased PGE(2) production was mediated by constitutively high expression of 85-kDa cytosolic pho spholipase A(2) (cPLA(2)) and cyclooxygenase 2 (COX-2). The increased expression of cPLA(2) protein was mediated through elevated mRNA level s and activation of the cPLA(2) promoter. Induction of cPLA(2) promote r activity was blocked by expression of dominant-negative forms of Ras . Inhibition of Ras by the farnesyltransferase inhibitor BZA-5B inhibi ted prostaglandin synthesis in H2122 cells by decreasing expression of both cPLA(2) and COX-2. Finally, inhibitors of eicosanoid synthesis b locked anchorage-independent growth of NSCLC lines exhibiting Ki-Ras m utations. These results identify cPLA(2) as a novel Ras-inducible regu lator of eicosanoid synthesis that participates in cellular transforma tion.