title: Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways.
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.
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Tanzer
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Nufail
authors.initials: N
authors.lastname: Khan
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Rickard
authors.affiliation: Olivia Newton John Cancer Research Institute, Heidelberg, VIC 3084, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia.
authors.forename: Nima
authors.initials: N
authors.lastname: Etemadi
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Najoua
authors.initials: N
authors.lastname: Lalaoui
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Sukhdeep Kaur
authors.initials: SK
authors.lastname: Spall
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Hildebrand
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Segal
authors.affiliation: School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Miasari
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Diep
authors.initials: D
authors.lastname: Chau
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: WendyWei-Lynn
authors.initials: WL
authors.lastname: Wong
authors.affiliation: TetraLogic Pharmaceuticals Corporation, Malvern, PA 19355, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: McKinlay
authors.affiliation: TetraLogic Pharmaceuticals Corporation, Malvern, PA 19355, USA.
authors.forename: Srinivas K
authors.initials: SK
authors.lastname: Chunduru
authors.affiliation: TetraLogic Pharmaceuticals Corporation, Malvern, PA 19355, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Benetatos
authors.affiliation: TetraLogic Pharmaceuticals Corporation, Malvern, PA 19355, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Condon
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064113:CRISPR-Cas Systems / Q000235:genetics; D053455:Caspase 10 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002460:Cell Line; D000074049:Cytokine TWEAK / Q000494:pharmacology; D004357:Drug Synergism; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010421:Pentanoic Acids / Q000494:pharmacology; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D000074049:Cytokine TWEAK; D051034:Inhibitor of Apoptosis Proteins; D010421:Pentanoic Acids; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D007371:Interferon-gamma; C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053455:Caspase 10; D053181:Caspase 8