Ras pathway activation in malignant mesothelioma.
BACKGROUND
Mutations in Ras family genes are rare in malignant mesothelioma. The role of activation of the Ras signaling pathway in the pathogenesis of mesothelioma is not clear.


METHODS
We studied the activation status of the Ras pathway and the status of other Ras-associated kinases in a panel of human mesothelioma cell lines. In addition, we tested the effect of inhibition of several kinase pathways on mesothelioma cell proliferation. The potential role of kinase signaling on the regulation of cap-dependent translation was also studied.


RESULTS
In general, Ras-guanosine triphosphate (GTP) was higher in mesothelioma cell lines when compared with a nontransformed mesothelial cell line (LP9). Furthermore, known Ras effectors such as extracellular-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase were found to be active in most of the mesothelioma cell lines tested. Exposure to specific inhibitors of extracellular-regulated kinase 1/2 (U0126) and c-Jun N-terminal kinase (SP600125) significantly decreased the proliferation of H2596 and H2373 cells compared with mock-treated cells. SP600125-mediated c-Jun N-terminal kinase inhibition, but not extracellular-regulated kinase 1/2 inhibition, resulted in a decrease in phosphorylation of 4E-BP1, consequently decreasing cap-dependent activation.


CONCLUSIONS
These experiments provide a rationale for targeting Ras and associated signaling pathways in mesothelioma and also suggest cap-dependent translation as one mechanism by which Ras induces proliferation in this disease.
Patel
Manish R
MR
Division of Hematology-Oncology-Transplant, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Jacobson
Blake A
BA
De
Arpita
A
Frizelle
Sandra P
SP
Janne
Pasi
P
Thumma
Saritha C
SC
Whitson
Brian A
BA
Farassati
Faris
F
Kratzke
Robert A
RA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008654:Mesothelioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism