title: Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer.
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.
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK.
authors: J S
authors: JS
authors: Riley
authors: R
authors: R
authors: Hutchinson
authors: D G
authors: DG
authors: McArt
authors: N
authors: N
authors: Crawford
authors: C
authors: C
authors: Holohan
authors: I
authors: I
authors: Paul
authors: S
authors: S
authors: Van Schaeybroeck
authors: M
authors: M
authors: Salto-Tellez
authors: P G
authors: PG
authors: Johnston
authors: D A
authors: DA
authors: Fennell
authors: K
authors: K
authors: Gately
authors: K
authors: K
authors: O'Byrne
authors: R
authors: R
authors: Cummins
authors: E
authors: E
authors: Kay
authors: P
authors: P
authors: Hamilton
authors: I
authors: I
authors: Stasik
authors: D B
authors: DB
authors: Longley
mesh_terms: D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D012189:Retrospective Studies
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8