Induction of cytosolic phospholipase A₂ by oncogenic Ras in human non- small cell lung cancer

Mutations in Ras family members that confer oncogenic potential are frequently observed in specific human cancers. We report that human non- small cell lung cancer (NSCLC) lines that harbor oncogenic mutations in Ki- Ras (H460, A549, H2122) synthesized high levels of prostaglandin E₂ (PGE₂) compared with NSCLC lacking Ras mutations or non-transformed lung epithelial cells (BEAS-2B). This increased PGE₂ production was mediated by constitutively high expression of 85-kDa cytosolic phospholipase A₂ (cPLA₂) and cyclooxygenase 2 (COX-2). The increased expression of cPLA₂ protein was mediated through elevated mRNA levels and activation of the cPLA₂ promoter. Induction of cPLA₂ promoter activity was blocked by expression of dominant- negative forms of Ras. Inhibition of Ras by the farnesyltransferase inhibitor BZA-5B inhibited prostaglandin synthesis in H2122 cells by decreasing expression of both cPLA₂ and COX-2. Finally, inhibitors of eicosanoid synthesis blocked anchorage-independent growth of NSCLC lines exhibiting Ki- Ras mutations. These results identify cPLA₂ as a novel Ras-inducible regulator of eicosanoid synthesis that participates in cellular transformation.