NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis-inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5

  • Authors:
    • Kimberly A. Foster
    • Esther P. Jane
    • Daniel R. Premkumar
    • Alejandro Morales
    • Ian F. Pollack
  • View Affiliations

  • Published online on: June 5, 2015     https://doi.org/10.3892/ijo.2015.3035
  • Pages: 506-516
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Abstract

We previously observed that glioma cells are differentially sensitive to TRAIL-induced toxicity. Based on our observation that TRAIL-resistant glioma cell lines typically exhibited high levels of Akt activation, we hypothesized that inhibition of Akt signaling using the PI3 kinase inhibitor NVP-BKM120 could promote TRAIL-induced apoptosis in gliomas. We assessed this combination in established and primary cultured glioma cells. Combination treatment led to significant cellular death when compared to either drug alone, but had no effect in normal human astrocytes, and demonstrated activation of the caspase cascade. This enhanced apoptosis appears dependent upon the loss of mitochondrial membrane potential and the release of Smac/DIABLO, AIF and cytochrome c into the cytosol. The upregulation of Noxa and sequestration of Mcl-1 by Noxa were important factors for cell death. Knockdown of Noxa abrogated apoptosis and suggested dependency on Noxa in combination-induced apoptosis. BKM120 upregulated cell surface expression of death receptor 5 (DR5), but did not increase levels of the other major TRAIL receptor, death receptor 4 (DR4). This study demonstrates that antagonizing apoptosis-resistance pathways, such as the PI3/Akt pathway, in combination with death receptor activation, may induce cell death in TRAIL-resistant glioma.
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August-2015
Volume 47 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Foster KA, Jane EP, Premkumar DR, Morales A and Pollack IF: NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis-inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5. Int J Oncol 47: 506-516, 2015.
APA
Foster, K.A., Jane, E.P., Premkumar, D.R., Morales, A., & Pollack, I.F. (2015). NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis-inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5. International Journal of Oncology, 47, 506-516. https://doi.org/10.3892/ijo.2015.3035
MLA
Foster, K. A., Jane, E. P., Premkumar, D. R., Morales, A., Pollack, I. F."NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis-inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5". International Journal of Oncology 47.2 (2015): 506-516.
Chicago
Foster, K. A., Jane, E. P., Premkumar, D. R., Morales, A., Pollack, I. F."NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis-inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5". International Journal of Oncology 47, no. 2 (2015): 506-516. https://doi.org/10.3892/ijo.2015.3035