E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin

MacKay, C., Carroll, E., Ibrahim, A. F.M., Garg, A., Inman, G. J. , Hay, R. T. and Alpi, A. F. (2014) E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin. Cancer Research, 74(8), pp. 2246-2257. (doi: 10.1158/0008-5472.CAN-13-2131) (PMID:24686174) (PMCID:PMC3990471)

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he genotoxin cisplatin is commonly used in chemotherapy to treat solid tumors, yet our understanding of the mechanism underlying the drug response is limited. In a focused siRNA screen, using an siRNA library targeting genes involved in ubiquitin and ubiquitin-like signaling, we identified the E3 ubiquitin ligase HOIP as a key regulator of cisplatin-induced genotoxicity. HOIP forms, with SHARPIN and HOIL-1L, the linear ubiquitin assembly complex (LUBAC). We show that cells deficient in the HOIP ligase complex exhibit hypersensitivity to cisplatin. This is due to a dramatic increase in caspase-8/caspase-3–mediated apoptosis that is strictly dependent on ATM-, but not ATR-mediated DNA damage checkpoint activation. Moreover, basal and cisplatin-induced activity of the stress response kinase JNK is enhanced in HOIP-depleted cells and, conversely, JNK inhibition can increase cellular resistance to cisplatin and reverse the apoptotic hyperactivation in HOIP-depleted cells. Furthermore, we show that HOIP depletion sensitizes cancer cells, derived from carcinomas of various origins, through an enhanced apoptotic cell death response. We also provide evidence that ovarian cancer cells classified as cisplatin-resistant can regain sensitivity following HOIP downregulation. Cumulatively, our study identifies a HOIP-regulated antiapoptotic signaling pathway, and we envisage HOIP as a potential target for the development of combinatorial chemotherapies to potentiate the efficacy of platinum-based anticancer drugs.

Item Type:Articles
Additional Information:This work was supported by the Scottish Institute for Cell Signalling and the pharmaceutical companies supporting DSTT (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck–Serono, and Pfizer), and, in part, by the Wellcome Trust Strategic Award grant 097945/B/11/Z. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Glasgow Author(s) Enlighten ID:Inman, Professor Gareth
Authors: MacKay, C., Carroll, E., Ibrahim, A. F.M., Garg, A., Inman, G. J., Hay, R. T., and Alpi, A. F.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN (Online):1538-7445
Published Online:31 March 2014

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