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

Ho Young Lee, Harish Srinivas, Dianren Xia, Yiling Lu, Robert Superty, Ruth LaPushin, Candelaria Gomez-Manzano, Anna Maria Gal, Garrett L. Walsh, Thomas Force, Kohjiro Ueki, Gordon B. Mills, Jonathan M. Kurie

    Research output: Contribution to journalArticlepeer-review

    53 Scopus citations

    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 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.

    Original languageEnglish (US)
    Pages (from-to)23630-23638
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume278
    Issue number26
    DOIs
    StatePublished - Jul 27 2003

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Fingerprint Dive into the research topics of 'Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH<sub>2</sub>-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival'. Together they form a unique fingerprint.

    Cite this