Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways Academic Article uri icon


  • 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.


  • 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, Wendy Wei-Lynn
  • McKinlay, Mark
  • Chunduru, Srinivas K
  • Benetatos, Christopher A
  • Condon, Stephen M
  • Vince, James E
  • Herold, Marco J
  • Silke, John

publication date

  • 2017

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