title: 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.
abstract: 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.
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Harish
authors.initials: H
authors.lastname: Srinivas
authors.forename: Dianren
authors.initials: D
authors.lastname: Xia
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Robert
authors.initials: R
authors.lastname: Superty
authors.forename: Ruth
authors.initials: R
authors.lastname: LaPushin
authors.forename: Candelaria
authors.initials: C
authors.lastname: Gomez-Manzano
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gal
authors.forename: Garrett L
authors.initials: GL
authors.lastname: Walsh
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D017209:Apoptosis; D002470:Cell Survival; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D009154:Mutation; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human