PKC-eta mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways.

Abstract

We previously demonstrated that protein kinase C-eta (PKC-eta) mediates a phorbol 12-myristate-13-acetate (PMA)-induced proliferative response in human glioblastoma (GBM) cells. In this report, we show that PMA-stimulated activation of PKC-eta in U-251 GBM cells resulted in activation of both Akt and the mammalian target of rapamycin (mTOR) signaling pathways and an increase in cell proliferation. Expression of a kinase dead PKC-eta (PKC-etaKR) construct reduced the basal and PMA-evoked proliferation of PKC-eta-expressing U-251 GBM cells, as well as abrogated the PMA-induced activation of Akt, mTOR, and the mTOR targets 4E-BP1 and STAT-3. Treatment of cells with the PI-3 kinase inhibitor LY294002 (10 muM) or the mTOR inhibitor rapamycin (10 nM) also reduced PMA-induced proliferation and cell-cycle progression. Expression of a constitutively active PKC-eta (PKC-etaDeltaNPS) construct in a GBM cell line with no endogenous PKC-eta (U-1242) also provided evidence that PKC-eta targets the Akt and mTOR signaling pathways. Moreover, activation of 4E-BP1 and STAT-3 in both PMA-treated U-251 and PKC-etaDeltaNPS-expressing U-1242 GBM cells was inhibited by rapamycin. However, activation of Akt, but not mTOR was inhibited by the PI-3 kinase inhibitor LY294002. This study identifies Akt and mTOR as downstream targets of PKC-eta that are involved in GBM cell proliferation.

• Authors: Sean E Aeder, Patrick M Martin, Jae-Won Soh, Isa M Hussaini
• Journal: Oncogene (Oncogene) Vol. 23 Issue 56 Pg. 9062-9 (Dec 02 2004) ISSN: 0950-9232 [Print] England
• PMID: 15489897 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chromones
• Enzyme Inhibitors
• Morpholines
• Proto-Oncogene Proteins
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Protein Kinases
• protein kinase C eta
• MTOR protein, human
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Protein Kinase C
• Tetradecanoylphorbol Acetate
• Sirolimus

Topics

• Brain Neoplasms (enzymology, metabolism, pathology)
• Cell Cycle (drug effects)
• Chromones (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Glioblastoma (enzymology, metabolism, pathology)
• Humans
• Morpholines (pharmacology)
• Protein Kinase C (metabolism)
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Signal Transduction
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases
• Tetradecanoylphorbol Acetate (pharmacology)