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Phorbol 12-myristate 13-acetate and serum synergize to promote rapamycin-insensitive cell proliferation via protein kinase C-eta

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Abstract

Previously, we have shown that PKC-η (protein kinase C-eta) positively regulates glioblastoma proliferation and confers resistance to irradiation-induced apoptosis. In this study, we investigated the efficacy of rapamycin in inhibiting cell proliferation in two glioblastoma cell lines U-251MG (PKC-η expressing) and U-1242MG (PKC-η deficient) following PKC-η activation. In U-251MG cells, rapamycin (10 nM) treatment was less effective as an antiproliferative agent when cells were concurrently stimulated with 10% serum and phorbol 12-myristate 13-acetate (PMA, 100 nM), a potent activator of PKC isozymes. Rapamycin-insensitive growth was owing to PKC-η, as U-1242MG and U-251MG cells infected with a kinase-dead form of PKC-η (U-251kr) were susceptible to rapamycin-induced inhibition of cell proliferation. Furthermore, U-251MG cells transfected with PKC-η antisense oligonucleotides were sensitive to rapamycin. PKC-η-expressing cells stimulated with PMA maintained p70S6K phosphorylation on Thr389 and phosphorylation of rpS6 (ser235/36), suggesting p70S6K kinase activity was still intact. Inhibition of p70S6K expression with small interfering RNA oligonucleotides inhibited cell proliferation greater than 50% in the presence of a combination of PMA and serum. Additionally, p70S6K co-precipitated with PKC-η, suggesting a physical interaction between PKC-η and p70S6K regulates the observed phosphorylation. Taken together, these data demonstrate that rapamycin-insensitive glioblastoma proliferation involves PKC-η signaling.

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Acknowledgements

We thank Joan Carpenter, Gerald Redpath and Anna Riggan for technical support. This work was funded by a UNCF/MERCK Fellowship to Patrick Martin and by NIH Grant RO1 CA90851 to IM Hussaini. CA Chrestensen was supported by a Medical Research and Material Command Grant (DAMD 17-03-1-0555) and TW Sturgill was supported by NIH Grant GM62890.

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Authors and Affiliations

  1. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    P M Martin, S E Aeder & I M Hussaini

  2. Department of Pharmacology, University of Virginia, Charlottesville, VA, USA

    C A Chrestensen & T W Sturgill

  3. Department of Neuroscience, University of Virginia, Charlottesville, VA, USA

    I M Hussaini

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  1. P M Martin
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  2. S E Aeder
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Correspondence to P M Martin.

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Martin, P., Aeder, S., Chrestensen, C. et al. Phorbol 12-myristate 13-acetate and serum synergize to promote rapamycin-insensitive cell proliferation via protein kinase C-eta. Oncogene 26, 407–414 (2007). https://doi.org/10.1038/sj.onc.1209791

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