SAHA overcomes FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma..pdf (1.06 MB)
SAHA overcomes FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma
journal contribution
posted on 2015-07-13, 15:59 authored by N. Crawford, I. Stasik, C. Holohan, J. Majkut, M. McGrath, P. G. Johnston, G. Chessari, G. A. Ward, D. J. Waugh, Dean A. Fennell, D. B. LongleyMalignant pleural mesothelioma (MPM) is a highly pro-inflammatory malignancy that is rapidly fatal and increasing in incidence. Cytokine signaling within the pro-inflammatory tumor microenvironment makes a critical contribution to the development of MPM and its resistance to conventional chemotherapy approaches. SMAC mimetic compounds (SMCs) are a promising class of anticancer drug that are dependent on tumor necrosis factor alpha (TNFα) signaling for their activity. As circulating TNFα expression is significantly elevated in MPM patients, we examined the sensitivity of MPM cell line models to SMCs. Surprisingly, all MPM cell lines assessed were highly resistant to SMCs either alone or when incubated in the presence of clinically relevant levels of TNFα. Further analyses revealed that MPM cells were sensitized to SMC-induced apoptosis by siRNA-mediated downregulation of the caspase 8 inhibitor FLIP, an antiapoptotic protein overexpressed in several cancer types including MPM. We have previously reported that FLIP expression is potently downregulated in MPM cells in response to the histone deacetylase inhibitor (HDACi) Vorinostat (SAHA). In this study, we demonstrate that SAHA sensitizes MPM cells to SMCs in a manner dependent on its ability to downregulate FLIP. Although treatment with SMC in the presence of TNFα promoted interaction between caspase 8 and the necrosis-promoting RIPK1, the cell death induced by combined treatment with SAHA and SMC was apoptotic and mediated by caspase 8. These results indicate that FLIP is a major inhibitor of SMC-mediated apoptosis in MPM, but that this inhibition can be overcome by the HDACi SAHA.
History
Citation
Cell Death and Disease, 2013, 4, e733Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular MedicineVersion
- VoR (Version of Record)
Published in
Cell Death and DiseasePublisher
Nature Publishing Group: Open Access Journals for Associazione Differenziamento e Morte Cellulareeissn
2041-4889Acceptance date
2013-06-07Copyright date
2013Available date
2015-07-13Publisher DOI
Publisher version
http://www.nature.com/cddis/journal/v4/n7/full/cddis2013258a.htmlLanguage
enAdministrator link
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Keywords
Antineoplastic AgentsCASP8 and FADD-Like Apoptosis Regulating ProteinCaspase 3Caspase 8Cell Line, TumorCisplatinDown-RegulationDrug Resistance, NeoplasmDrug Screening Assays, AntitumorDrug SynergismEnzyme ActivationHistone Deacetylase InhibitorsHumansHydroxamic AcidsInhibitor of Apoptosis ProteinsMesotheliomaMolecular MimicryPleural NeoplasmsPoly(ADP-ribose) PolymerasesReceptor-Interacting Protein Serine-Threonine Kinases