Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent

Hurwitz, J. L., Stasik, I., Kerr, E. M., Holohan, C., Redmond, K. M., McLaughlin, K. M., Busacca, S., Barbone, D., Broaddus, V. C., Gray, S. G., O'Byrne, Kenneth J., Johnston, P. G., Fennell, D. A., & Longley, D. B. (2012) Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent. European Journal of Cancer, 48(7), pp. 1096-1107.

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Introduction: Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma. We examined the roles of FLIP and caspase 8 in regulating SAHA-induced apoptosis in MPM.

Methods: The mechanism of SAHA-induced apoptosis was assessed in 7 MPM cell lines and in a multicellular spheroid model. SiRNA and overexpression approaches were used, and cell death was assessed by flow cytometry, Western blotting and clonogenic assays. Results: RNAi-mediated FLIP silencing resulted in caspase 8-dependent apoptosis in MPM cell line models. SAHA potently down-regulated FLIP protein expression in all 7 MPM cell lines and in a multicellular spheroid model of MPM. In 6/7 MPM cell lines, SAHA treatment resulted in significant levels of apoptosis induction. Moreover, this apoptosis was caspase 8-dependent in all six sensitive cell lines. SAHA-induced apoptosis was also inhibited by stable FLIP overexpression. In contrast, down-regulation of HR23B, a candidate predictive biomarker for HDAC inhibitors, significantly inhibited SAHA-induced apoptosis in only 1/6 SAHA-sensitive MPM cell lines. Analysis of MPM patient samples demonstrated significant inter-patient variations in FLIP and caspase 8 expressions. In addition, SAHA enhanced cisplatin-induced apoptosis in a FLIP-dependent manner.

Conclusions: These results indicate that FLIP is a major target for SAHA in MPM and identifies FLIP, caspase 8 and associated signalling molecules as candidate biomarkers for SAHA in this disease. © 2011 Elsevier Ltd. All rights reserved.

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ID Code: 65125
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Caspase 8, FLIP, HDAC inhibitors, Mesothelioma, SAHA/Vorinostat, biological marker, cisplatin, FLICE inhibitory protein, vorinostat, apoptosis, article, cancer cell culture, down regulation, drug effect, drug potency, drug potentiation, malignant mesothelioma, priority journal, Apoptosis Regulatory Proteins, CASP8 and FADD-Like Apoptosis Regulating Protein, Cell Line, Tumor, DNA Repair Enzymes, DNA-Binding Proteins, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Male, Pleural Neoplasms, RNA Interference, Spheroids, Cellular
DOI: 10.1016/j.ejca.2011.11.009
ISSN: 0959-8049
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 Pergamon
Deposited On: 05 Dec 2013 01:10
Last Modified: 19 Dec 2013 04:14

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