Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Riley, J. S., Hutchinson, R., McArt, D. G., Crawford, N., Holohan, C., Paul, I., Van Schaeybroeck, S., Salto-Tellez, M., Johnston, P. G., Fennell, D. A., Gately, K., O'Byrne, K., Cummins, R., Kay, E., Hamilton, P., Stasik, I., & Longley, D. B. (2013) Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer. Cell Death and Disease, 4(e951).

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Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

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ID Code: 67781
Item Type: Journal Article
Refereed: Yes
Keywords: caspase-8, FLIP, HDAC inhibitor, non-small cell lung cancer, TRAIL, acy 775, birinapant, caspase 3, caspase 8, cisplatin, death receptor, entinostat, FLICE inhibitory protein, histone deacetylase 1, histone deacetylase 2, histone deacetylase 3, histone deacetylase 6, histone deacetylase inhibitor, panobinostat, procaspase 8, tumor necrosis factor related apoptosis inducing ligand, tumor necrosis factor related apoptosis inducing ligand receptor, unclassified drug, vorinostat, X linked inhibitor of apoptosis, adult, aged, article, cancer cell culture, cancer prognosis, cancer resistance, cancer surgery, cancer survival, cell nucleus, cell viability, cytoplasm, down regulation, drug potentiation, enzyme activation, female, follow up, gene overexpression, human, human tissue, immunohistochemistry, lung non small cell cancer, major clinical study, male, middle aged, overall survival, priority journal, protein expression, protein localization, protein targeting, retrospective study, signal transduction, tissue microarray, very elderly
DOI: 10.1038/cddis.2013.481
ISSN: 2041-4889
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
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 2013 Macmillan Publishers Limited
Copyright Statement: Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial- NoDerivs 3.0 Unported License. To view a copy of this license, visit
Deposited On: 25 Feb 2014 03:54
Last Modified: 26 Feb 2014 12:04

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