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

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

Authors
  • J. S. Riley
  • R. Hutchinson
  • D. G. McArt
  • N. Crawford
  • C. Holohan
  • I. Paul
  • S. Van Schaeybroeck
  • M. Salto-Tellez
  • P. G. Johnston
  • D. A. Fennell
  • K. Gately
  • K. O'Byrne
  • R. Cummins
  • E. Kay
  • P. Hamilton
  • I. Stasik
  • D. B. Longley
Publisher
Nature Publishing Group
Keywords

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.

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