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Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer
- Source :
- Cell Death & Disease, Cell Death and Disease, Riley, J S, Hutchinson, R, McArt, D G, Crawford, N, Holohan, C, Paul, I, Van Schaeybroeck, S, Salto-Tellez, M, Johnston, P, Fennell, D, 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 & Disease, vol. 4, no. 12, e951, pp. e951 . https://doi.org/10.1038/cddis.2013.481
- Publication Year :
- 2013
- Publisher :
- Nature Publishing Group, 2013.
-
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.
- Subjects :
- Cancer Research
C131
Cell Survival
FLIP
Blotting, Western
Immunology
Cell
CASP8 and FADD-Like Apoptosis Regulating Protein
TRAIL
In Vitro Techniques
Biology
Caspase 8
Q1
caspase-8
Cellular and Molecular Neuroscience
chemistry.chemical_compound
SDG 3 - Good Health and Well-being
HDAC inhibitor
Carcinoma, Non-Small-Cell Lung
medicine
Humans
Lung cancer
non-small cell lung cancer
Retrospective Studies
Cisplatin
Entinostat
B131
B132
A100
Cell Biology
Flow Cytometry
medicine.disease
Molecular biology
respiratory tract diseases
medicine.anatomical_structure
chemistry
Flip
Cell culture
Apoptosis
Cancer research
Original Article
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease, Cell Death and Disease, Riley, J S, Hutchinson, R, McArt, D G, Crawford, N, Holohan, C, Paul, I, Van Schaeybroeck, S, Salto-Tellez, M, Johnston, P, Fennell, D, 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 & Disease, vol. 4, no. 12, e951, pp. e951 . https://doi.org/10.1038/cddis.2013.481
- Accession number :
- edsair.doi.dedup.....94d87cf6a3548286c899f24353f11bcf