Combination of IAP antagonist and IFNgamma activates novel caspase-10- and RIPK1-dependent cell death pathways
- Tanzer, MC; Khan, N; Rickard, JA; Etemadi, N; Lalaoui, N; Spall, SK; Hildebrand, JM; Segal, D; Miasari, M; Chau, D; Wong, WL; McKinlay, M; Chunduru, SK; Benetatos, CA; Condon, SM; Vince, JE; Herold, MJ; Silke, J;
Publication Year 2017-03, Volume 24, Issue #3, Page 481-491
- Journal Title
- Cell Death and Differentiation
- Publication Type
- Journal Article
- Peptido-mimetic inhibitor of apoptosis protein (IAP) antagonists (Smac mimetics (SMs)) can kill tumour cells by depleting endogenous IAPs and thereby inducing tumour necrosis factor (TNF) production. We found that interferon-gamma (IFNgamma) synergises with SMs to kill cancer cells independently of TNF- and other cell death receptor signalling pathways. Surprisingly, CRISPR/Cas9 HT29 cells doubly deficient for caspase-8 and the necroptotic pathway mediators RIPK3 or MLKL were still sensitive to IFNgamma/SM-induced killing. Triple CRISPR/Cas9-knockout HT29 cells lacking caspase-10 in addition to caspase-8 and RIPK3 or MLKL were resistant to IFNgamma/SM killing. Caspase-8 and RIPK1 deficiency was, however, sufficient to protect cells from IFNgamma/SM-induced cell death, implying a role for RIPK1 in the activation of caspase-10. These data show that RIPK1 and caspase-10 mediate cell death in HT29 cells when caspase-8-mediated apoptosis and necroptosis are blocked and help to clarify how SMs operate as chemotherapeutic agents.
- Springer Nature
- WEHI Research Division(s)
- Molecular Genetics Of Cancer; Inflammation; Chemical Biology; Cell Signalling And Cell Death
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-04-06 09:27:19Last Modified: 2017-04-06 11:02:45