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TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation

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Abstract

Patients with malignant gliomas have a poor prognosis and new treatment paradigms are needed against this disease. TRAIL/Apo2L selectively induces apoptosis in malignant cells sparing normal cells and is hence of interest as a potential therapeutic agent against gliomas. To determine the factors that modulate sensitivity to TRAIL, we examined the differences in TRAIL-activated signaling pathways in glioma cells with variable sensitivities to the agent. Apoptosis in response to TRAIL was unrelated to DR5 expression or endogenous p53 status in a panel of 8 glioma cell lines. TRAIL activated the extrinsic (cleavage of caspase-8, caspase-3 and PARP) and mitochondrial apoptotic pathways and reduced FLIP levels. It also induced caspase-dependent JNK activation, which did not influence TRAIL-induced apoptosis. Because the pro-survival PI3K/Akt pathway is highly relevant to gliomas, we assessed whether Akt could protect against TRAIL-induced apoptosis. Pretreatment with SH-6, a novel Akt inhibitor, enhanced TRAIL-induced apoptosis, suggesting a protective role for Akt. Conversely, TRAIL induced caspase-dependent cleavage of Akt neutralizing its anti-apoptotic effects. These results demonstrate that TRAIL-induced apoptosis in gliomas involves both activation of death pathways and downregulation of survival pathways. Additional studies are warranted to determine the therapeutic potential of TRAIL against gliomas.

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Authors and Affiliations

  1. Departments of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 7700, USA

    V. K. Puduvalli, J. Nangia & R. Xu

  2. Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 7700, USA

    D. Sampath

  3. Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 7700, USA

    J. M. Bruner

  4. Department of Neurology, University of Ioaninna, Ioaninna, Greece

    A. P. Kyritsis

Authors
  1. V. K. Puduvalli
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  2. D. Sampath
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  3. J. M. Bruner
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  4. J. Nangia
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  5. R. Xu
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  6. A. P. Kyritsis
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Correspondence to V. K. Puduvalli.

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Supported in part by the NIH grant PO1 CA55261

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Puduvalli, V.K., Sampath, D., Bruner, J.M. et al. TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation. Apoptosis 10, 233–243 (2005). https://doi.org/10.1007/s10495-005-6078-3

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