Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing

Wilson, T. R., Redmond, K. M., McLaughlin, K. M., Crawford, N., Gately, K., O'Byrne, Kenneth J., Le-Clorrenec, C., Holohan, C., Fennell, D. A., Johnston, P. G., & Longley, D. B. (2009) Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing. Cell Death and Differentiation, 16(10), pp. 1352-1361.

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We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptosis induced by FLIP silencing was mediated by the TRAIL death receptors DR4 and DR5, but was not dependent on ligation of the receptors by TRAIL. Furthermore, the apoptosis induced by FLIP silencing was dependent on the overexpression of procaspase 8 in NSCLC cells. Moreover, in NSCLC cells, but not in normal cells, FLIP silencing induced co-localization of DR5 and ceramide, and disruption of this co-localization abrogated apoptosis. FLIP silencing supra-additively increased TRAIL-induced apoptosis of NSCLC cells; however, normal lung cells were resistant to TRAIL, even when FLIP was silenced. Importantly, FLIP silencing sensitized NSCLC cells but not normal cells to chemotherapy in vitro, and silencing FLIP in vivo retarded NSCLC xenograft growth and enhanced the anti-tumour effects of cisplatin. Collectively, our results suggest that due to frequent procaspase 8 overexpression, NSCLCs may be particularly sensitive to FLIP-targeted therapies.

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ID Code: 65783
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: ceramide, cisplatin, death receptor 4, death receptor 5, FLICE inhibitory protein, paclitaxel, procaspase 8, protein Bid, small interfering RNA, adult, aged, animal experiment, animal model, antineoplastic activity, apoptosis, article, cancer cell, cancer growth, clinical article, controlled study, down regulation, enzyme activation, female, gene location, gene overexpression, gene silencing, human, human cell, in vitro study, lung non small cell cancer, male, mouse, nonhuman, priority journal, tumor xenograft, Animals, Antineoplastic Agents, BH3 Interacting Domain Death Agonist Protein, Carcinoma, Non-Small-Cell Lung, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 8, Cell Line, Tumor, Enzyme Precursors, Flow Cytometry, Humans, Lung Neoplasms, Mice, Mice, Nude, Receptors, TNF-Related Apoptosis-Inducing Ligand, RNA Interference, RNA, Small Interfering, TNF-Related Apoptosis-Inducing Ligand, Transplantation, Heterologous
DOI: 10.1038/cdd.2009.76
ISSN: 1350-9047
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2009 Nature Publishing Group
Deposited On: 08 Jan 2014 04:19
Last Modified: 13 Mar 2014 01:02

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