Journal article
Combination of IAP antagonist and IFNγ activates novel caspase-10-and RIPK1-dependent cell death pathways
MC Tanzer, N Khan, JA Rickard, N Etemadi, N Lalaoui, SK Spall, JM Hildebrand, D Segal, M Miasari, D Chau, WWL Wong, M McKinlay, SK Chunduru, CA Benetatos, SM Condon, JE Vince, MJ Herold, J Silke
Cell Death and Differentiation | NATURE PUBLISHING GROUP | Published : 2017
DOI: 10.1038/cdd.2016.147
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, suf..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank Toru Okamoto for the pFTRE 3G construct, David Baltimore for lentiviral packaging constructs, Theo Mantamadiotis for the ERT2 construct, Robert Gerl for early work with the GAL4 ERT2 VP16 system, Henning Walczak for the TRAIL ligand, Tracy Putoczki for LIM2837, LIM1215, SW480, LIM2560, LIM2405, SW481 cells, Conor Kearney for MEWO, ME-RM, SK-Mel-28, ME4405,HT-144, Oliver Sieber for SKCO1, HCT116, OLDI, LIM2099 cells, Ben Kile for Ifnar<SUP>-/-</SUP> mouse tails, Paul Hertzog for Pkr<SUP>-/-</SUP>, PKR K271R and Ifnar<SUP>-/-</SUP> tails, Seth Masters for Casp1<SUP>-/-</SUP> tails, Andreas Strasser forCasp8<SUP>-/-</SUP> /Mlkl<SUP>-/-</SUP> tails, Hans-Uwe Simon for the pLKO. 1 construct encoding for the shRNA ATG5, James Murphy and Guillaume Lessene for Compound 1 (MLKL inhibitor). Andrew Kueh and Stephen Wilcox for helping with the next-generation sequencing. J Silke is funded by the NHMRC (433013, 541901 and 541902). MC Tanzer is funded by the Victorian International Research Scholarship. Fc-TNFSF ligand DNA was provided by J Tschopp (University of Lausanne, Lausanne, Switzerland). We thank Wendy Cook and David Vaux for their input and guidance in editing this paper.