INTRODUCTION: The X-chromosome-linked inhibitor of apoptosis protein (XIAP) prevents apoptosis from activated transmembrane death receptors and confers tumour resistance to irradiation and chemotherapy. Despite the important oncologic implications, data concerning glioblastoma in this regard are few and isolated. The objective of this study was to examine the role of XIAP in the signalling pathway of TRAIL (tumour necrosis factor-related apoptosis-inducing ligand)-mediated apoptosis in chemoresistant human glioblastoma cells. METHOD: Downregulators of XIAP, low-dose cisplatin, etoposide (VP 16) or second mitochondria-derived activator of caspase (Smac)-Tat peptide, were applied to 2 chemoresistant glioblastoma cell lines of fresh isolates to identify the impact of these sensitizing agents on the cytotoxicity of TRAIL. Hoechst staining for apoptotic nuclear morphology and Western blot analysis for the corresponding levels of proteins that regulate apoptotic pathways including XIAP were performed. The involvement of mitochondrial pathways marked by the release of cytochrome c or Smac/direct IAP (inhibitor of apoptosis protein)-binding protein with low P1 (DIABLO), or both, was assessed by confocal fluorescence microscopy. RESULTS: Downregulators of XIAP induced apoptosis in a dose-dependent manner with TRAIL in 1 chemoresistant glioblastoma cell line. Here, XIAP downregulation modulated by Smac-Tat peptide resulted in increased TRAIL-induced cell death. In addition, TRAIL was shown to enhance the translocation of Smac/DIABLO from mitochondria to the cytosol in cells that underwent apoptosis, which in turn neutralized XIAP activity. In comparison, the second chemoresistant glioblastoma cell line showed no regulatory XIAP effect. This finding correlates with the upstream effect of mutant p53 and BCL-X(L) status that were upregulated in this chemoresistant cell line. CONCLUSION: These results support the use of selective or tailored therapeutic strategies that synergistically sensitize chemoresistant glioblastoma to TRAIL-mediated apoptosis by administering appropriate XIAP downregulating agents.
INTRODUCTION: The X-chromosome-linked inhibitor of apoptosis protein (XIAP) prevents apoptosis from activated transmembrane death receptors and confers tumour resistance to irradiation and chemotherapy. Despite the important oncologic implications, data concerning glioblastoma in this regard are few and isolated. The objective of this study was to examine the role of XIAP in the signalling pathway of TRAIL (tumour necrosis factor-related apoptosis-inducing ligand)-mediated apoptosis in chemoresistant humanglioblastoma cells. METHOD: Downregulators of XIAP, low-dose cisplatin, etoposide (VP 16) or second mitochondria-derived activator of caspase (Smac)-Tat peptide, were applied to 2 chemoresistant glioblastoma cell lines of fresh isolates to identify the impact of these sensitizing agents on the cytotoxicity of TRAIL. Hoechst staining for apoptotic nuclear morphology and Western blot analysis for the corresponding levels of proteins that regulate apoptotic pathways including XIAP were performed. The involvement of mitochondrial pathways marked by the release of cytochrome c or Smac/direct IAP (inhibitor of apoptosis protein)-binding protein with low P1 (DIABLO), or both, was assessed by confocal fluorescence microscopy. RESULTS: Downregulators of XIAP induced apoptosis in a dose-dependent manner with TRAIL in 1 chemoresistant glioblastoma cell line. Here, XIAP downregulation modulated by Smac-Tat peptide resulted in increased TRAIL-induced cell death. In addition, TRAIL was shown to enhance the translocation of Smac/DIABLO from mitochondria to the cytosol in cells that underwent apoptosis, which in turn neutralized XIAP activity. In comparison, the second chemoresistant glioblastoma cell line showed no regulatory XIAP effect. This finding correlates with the upstream effect of mutant p53 and BCL-X(L) status that were upregulated in this chemoresistant cell line. CONCLUSION: These results support the use of selective or tailored therapeutic strategies that synergistically sensitize chemoresistant glioblastoma to TRAIL-mediated apoptosis by administering appropriate XIAP downregulating agents.
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Authors: David S Ziegler; Renee D Wright; Santosh Kesari; Madeleine E Lemieux; Mary A Tran; Monish Jain; Leigh Zawel; Andrew L Kung Journal: J Clin Invest Date: 2008-09 Impact factor: 14.808
Authors: D M Ashley; C D Riffkin; M M Lovric; T Mikeska; A Dobrovic; J A Maxwell; H S Friedman; K J Drummond; A H Kaye; H K Gan; T G Johns; C J Hawkins Journal: Br J Cancer Date: 2008-07-01 Impact factor: 7.640