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.
Heasley
L E
LE
Department of Medicine, University of Colorado Health Science Center, Denver, Colorado 80262, USA.
Thaler
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Nicks
M
M
Price
B
B
Skorecki
K
K
Nemenoff
R A
RA
D002289:Carcinoma, Non-Small-Cell Lung; D002460:Cell Line; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000201:enzymology; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction; D004848:Epithelium; D011905:Genes, ras; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D007700:Kinetics; D008168:Lung; D008175:Lung Neoplasms; D008565:Membrane Proteins; D010741:Phospholipases A / Q000096:biosynthesis*; D054467:Phospholipases A2; D017354:Point Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D015232:Dinoprostone