Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

Paul, I., Chacko, A. D., Stasik, I., Busacca, S., Crawford, N., McCoy, F., McTavish, N., Wilson, B., Barr, M., O'Byrne, K. J., Longley, D. B., & Fennell, D. A. (2012) Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer. Cell Death & Disease, 3(e449).

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Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

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13 citations in Scopus
12 citations in Web of Science®
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ID Code: 67778
Item Type: Journal Article
Refereed: Yes
Keywords: Apoptosis/drug effects, Carcinoma, Non-Small-Cell Lung/drug therapy/ enzymology/genetics/physiopathology, Caspase 8/genetics/ metabolism, Cell Line, Tumor, Cisplatin, Drug Resistance, Neoplasm, Gene Expression Regulation, Enzymologic/ drug effects, Gene Expression Regulation, Neoplastic/drug effects, Humans, Lung Neoplasms/drug therapy/ enzymology/genetics/physiopathology, Protein Processing, Post-Translational/drug effects
DOI: 10.1038/cddis.2012.186
ISSN: 2041-4889
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
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 2012 Macmillan Publishers Limited
Copyright Statement: Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit
Deposited On: 25 Feb 2014 05:31
Last Modified: 18 Mar 2014 05:56

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