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

J S Riley, R Hutchinson, D G McArt, N Crawford, C Holohan, I Paul, S Van Schaeybroeck, M Salto-Tellez, Patrick Johnston, Dean Fennell, K Gately, K O'Byrne, R Cummins, E Kay, P Hamilton, I Stasik, D B Longley

Research output: Contribution to journalArticle

43 Citations (Scopus)
178 Downloads (Pure)

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.
Original languageEnglish
Article numbere951
Pages (from-to)e951
JournalCell, Death & Disease
Volume4
Issue number12
Early online date05 Dec 2013
DOIs
Publication statusPublished - Dec 2013

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

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