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X-linked inhibitor regulating TRAIL-induced apoptosis in chemoresistant human primary glioblastoma cells.
Clin Invest Med. 2003 Oct; 26(5):231-42.CI

Abstract

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.

Authors+Show Affiliations

Department of Oncology, University of Alberta, Edmonton, Alta. wilsonro@cancerboard.ab.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14596484

Citation

Roa, Wilson H., et al. "X-linked Inhibitor Regulating TRAIL-induced Apoptosis in Chemoresistant Human Primary Glioblastoma Cells." Clinical and Investigative Medicine. Medecine Clinique Et Experimentale, vol. 26, no. 5, 2003, pp. 231-42.
Roa WH, Chen H, Fulton D, et al. X-linked inhibitor regulating TRAIL-induced apoptosis in chemoresistant human primary glioblastoma cells. Clin Invest Med. 2003;26(5):231-42.
Roa, W. H., Chen, H., Fulton, D., Gulavita, S., Shaw, A., Th'ng, J., Farr-Jones, M., Moore, R., & Petruk, K. (2003). X-linked inhibitor regulating TRAIL-induced apoptosis in chemoresistant human primary glioblastoma cells. Clinical and Investigative Medicine. Medecine Clinique Et Experimentale, 26(5), 231-42.
Roa WH, et al. X-linked Inhibitor Regulating TRAIL-induced Apoptosis in Chemoresistant Human Primary Glioblastoma Cells. Clin Invest Med. 2003;26(5):231-42. PubMed PMID: 14596484.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - X-linked inhibitor regulating TRAIL-induced apoptosis in chemoresistant human primary glioblastoma cells. AU - Roa,Wilson H, AU - Chen,Hua, AU - Fulton,Dorcas, AU - Gulavita,Sunil, AU - Shaw,Andrew, AU - Th'ng,John, AU - Farr-Jones,Maxine, AU - Moore,Ronald, AU - Petruk,Kenneth, PY - 2003/11/5/pubmed PY - 2004/6/26/medline PY - 2003/11/5/entrez SP - 231 EP - 42 JF - Clinical and investigative medicine. Medecine clinique et experimentale JO - Clin Invest Med VL - 26 IS - 5 N2 - 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. SN - 0147-958X UR - https://www.unboundmedicine.com/medline/citation/14596484/X_linked_inhibitor_regulating_TRAIL_induced_apoptosis_in_chemoresistant_human_primary_glioblastoma_cells_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=14596484.ui DB - PRIME DP - Unbound Medicine ER -