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Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2017 Mar; Vol. 24 (3), pp. 481-491. Date of Electronic Publication: 2017 Jan 20. - Publication Year :
- 2017
-
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.
- Subjects :
- Animals
CRISPR-Cas Systems genetics
Caspase 10 chemistry
Caspase 10 genetics
Caspase 8 chemistry
Caspase 8 genetics
Caspase 8 metabolism
Caspase Inhibitors pharmacology
Cell Line
Cytokine TWEAK pharmacology
Drug Synergism
HT29 Cells
Humans
Inhibitor of Apoptosis Proteins antagonists & inhibitors
Interferon-gamma genetics
Interferon-gamma metabolism
Mice
Mice, Knockout
Pentanoic Acids pharmacology
Protein Kinases deficiency
Protein Kinases metabolism
Receptor-Interacting Protein Serine-Threonine Kinases deficiency
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Receptors, Tumor Necrosis Factor, Type I deficiency
Receptors, Tumor Necrosis Factor, Type I genetics
Receptors, Tumor Necrosis Factor, Type I metabolism
Recombinant Proteins biosynthesis
Recombinant Proteins isolation & purification
Recombinant Proteins pharmacology
Apoptosis drug effects
Caspase 10 metabolism
Inhibitor of Apoptosis Proteins metabolism
Interferon-gamma pharmacology
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 24
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 28106882
- Full Text :
- https://doi.org/10.1038/cdd.2016.147