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

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Abstract

We previously demonstrated that protein kinase C-η (PKC-η) 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-η 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-η (PKC-ηKR) construct reduced the basal and PMA-evoked proliferation of PKC-η-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 μ M) or the mTOR inhibitor rapamycin (10 nM) also reduced PMA-induced proliferation and cell-cycle progression. Expression of a constitutively active PKC-η (PKC-ηΔNPS) construct in a GBM cell line with no endogenous PKC-η (U-1242) also provided evidence that PKC-η targets the Akt and mTOR signaling pathways. Moreover, activation of 4E-BP1 and STAT-3 in both PMA-treated U-251 and PKC-ηΔNPS-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-η that are involved in GBM cell proliferation.

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Acknowledgements

We thank John B Schell and Alex M Ward for helpful advice on retrovirus construction. We also thank Janet V Cross and Stacey A Trotter for helpful discussions. This work was supported by Grant CA90851 (National Cancer Institute).

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Authors and Affiliations

  1. Department of Pathology and Neurology, University of Virginia, Charlottesville, 22908, VA, USA

    Sean E Aeder, Patrick M Martin & Isa M Hussaini

  2. Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 10032, New York, USA

    Jae-Won Soh

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  1. Sean E Aeder
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  2. Patrick M Martin
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Correspondence to Sean E Aeder.

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Aeder, S., Martin, P., Soh, JW. et al. PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene 23, 9062–9069 (2004). https://doi.org/10.1038/sj.onc.1208093

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  • DOI: https://doi.org/10.1038/sj.onc.1208093

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