TY - JOUR
T1 - 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
AU - Lee, Ho Young
AU - Srinivas, Harish
AU - Xia, Dianren
AU - Lu, Yiling
AU - Superty, Robert
AU - LaPushin, Ruth
AU - Gomez-Manzano, Candelaria
AU - Gal, Anna Maria
AU - Walsh, Garrett L.
AU - Force, Thomas
AU - Ueki, Kohjiro
AU - Mills, Gordon B.
AU - Kurie, Jonathan M.
PY - 2003/7/27
Y1 - 2003/7/27
N2 - 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 p85α regulatory subunit of PI3K (Δp85) induced apoptosis. Whereas PTEN and Δ85 both inhibited activation of AKT/protein kinase B, only Δp85 inhibited c-Jun NH2-terminal kinase (JNK) activity. Co-transfection of the constitutively active mutant Rac-1 (Val12), an upstream activator of JNK, abrogated Δp85-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.
AB - 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 p85α regulatory subunit of PI3K (Δp85) induced apoptosis. Whereas PTEN and Δ85 both inhibited activation of AKT/protein kinase B, only Δp85 inhibited c-Jun NH2-terminal kinase (JNK) activity. Co-transfection of the constitutively active mutant Rac-1 (Val12), an upstream activator of JNK, abrogated Δp85-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.
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U2 - 10.1074/jbc.M300997200
DO - 10.1074/jbc.M300997200
M3 - Article
C2 - 12714585
AN - SCOPUS:0038607408
SN - 0021-9258
VL - 278
SP - 23630
EP - 23638
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -