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

Riley, J.S. et al. (2013) Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer. Cell Death and Disease, 4, e951. (doi: 10.1038/cddis.2013.481)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Riley, Dr Joel
• Authors: 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., and Longley, D.B.
• Subjects: Q Science > Q Science (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Death and Disease
• Publisher: Nature Publishing Group
• ISSN: 2041-4889
• Copyright Holders: Copyright © 2013 Macmillan Publishers Limited
• First Published: First published in Cell Death and Disease 4:e951
• Publisher Policy: Reproduced under a Creative Commons License