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Title: Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways.
Austin Authors: Tanzer, Maria C;Khan, Nufail;Rickard, James A;Etemadi, Nima;Lalaoui, Najoua;Spall, Sukhdeep Kaur;Hildebrand, Joanne M;Segal, David;Miasari, Maria;Chau, Diep;Wong, WendyWei-Lynn;McKinlay, Mark;Chunduru, Srinivas K;Benetatos, Christopher A;Condon, Stephen M;Vince, James E;Herold, Marco J;Silke, John
Affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Institute of Experimental Immunology, University of Zurich, Zurich 8057, Switzerland
TetraLogic Pharmaceuticals Corporation, Malvern, PA, USA
Issue Date: Mar-2017
Date: 2017
Publication information: Cell death and differentiation 2017; 24(3): 481-491
Abstract: 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-γ (IFNγ) 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 IFNγ/SM-induced killing. Triple CRISPR/Cas9-knockout HT29 cells lacking caspase-10 in addition to caspase-8 and RIPK3 or MLKL were resistant to IFNγ/SM killing. Caspase-8 and RIPK1 deficiency was, however, sufficient to protect cells from IFNγ/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.
DOI: 10.1038/cdd.2016.147
Journal: Cell death and differentiation
PubMed URL: 28106882
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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