Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival
Authors
Lee, Ho-YoungSrinivas, Harish
Xia, Dianren
Lu, Yiling
Superty, Robert
LaPushin, Ruth
Gomez-Manzano, Candelaria
Gal, Annamaria
Walsh, Garrett L
Force, Thomas
Ueki, Kohjiro
Mills, Gordon B.
Kurie, Jonathan M.
Affiliation
University of Texas MD Anderson Cancer CenterNew England Medical Center
Harvard Medical School
Issue Date
2003-06-27
Metadata
Show full item recordAbstract
Cancer cells in which the PTEN lipid phosphatase gene is deleted have constitutively activated phosphatidylinositol 3-kinase (PI3K)-dependent signaling and require activation of this pathway for survival. In non-small cell lung cancer (NSCLC) cells, PI3K-dependent signaling is typically activated through mechanisms other than PTEN gene loss. The role of PI3K in the survival of cancer cells that express wild-type PTEN has not been defined. Here we provide evidence that H1299 NSCLC cells, which express wild-type PTEN, underwent proliferative arrest following treatment with an inhibitor of all isoforms of class I PI3K catalytic activity (LY294002) or overexpression of the PTEN lipid phosphatase. In contrast, overexpression of a dominant-negative mutant of the p85alpha regulatory subunit of PI3K (Deltap85) induced apoptosis. Whereas PTEN and Delta85 both inhibited activation of AKT/protein kinase B, only Deltap85 inhibited c-Jun NH2-terminal kinase (JNK) activity. Cotransfection of the constitutively active mutant Rac-1 (Val12), an upstream activator of JNK, abrogated Deltap85-induced lung cancer cell death, whereas constitutively active mutant mitogen-activated protein kinase kinase (MKK)-1 (R4F) did not. Furthermore, LY294002 induced apoptosis of MKK4-null but not wild-type mouse embryo fibroblasts. Therefore, we propose that, in the setting of wild-type PTEN, PI3K- and MKK4/JNK-dependent pathways cooperate to maintain cell survival.Citation
Lee, H.Y., Srinivas, H., Xia, D., Lu, Y. (2003) 'Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival', The Journal of biological chemistry, 278(26),pp.23630-23638PubMed ID
12714585Additional Links
http://www.ncbi.nlm.nih.gov/pubmed/12714585http://www.jbc.org/content/278/26/23630.full
Type
ArticleLanguage
enISSN
0021-9258ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M300997200