E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin

Craig MacKay, Eilís Carroll, Adel F. M. Ibrahim, Amit Garg, Gareth J. Inman, Ronald T. Hay, Arno F. Alpi

    Research output: Contribution to journalArticlepeer-review

    36 Citations (Scopus)

    Abstract

    The 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. Cancer Res; 74(8); 1-12. ©2014 AACR.
    Original languageEnglish
    Pages (from-to)2246-2257
    Number of pages12
    JournalCancer Research
    Volume74
    Issue number8
    DOIs
    Publication statusPublished - 15 Apr 2014

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