First Author | Tanzer MC | Year | 2017 |
Journal | Cell Death Differ | Volume | 24 |
Issue | 3 | Pages | 481-491 |
PubMed ID | 28106882 | Mgi Jnum | J:259265 |
Mgi Id | MGI:6140724 | Doi | 10.1038/cdd.2016.147 |
Citation | Tanzer MC, et al. (2017) Combination of IAP antagonist and IFNgamma activates novel caspase-10- and RIPK1-dependent cell death pathways. Cell Death Differ 24(3):481-491 |
abstractText | 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-gamma (IFNgamma) 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 IFNgamma/SM-induced killing. Triple CRISPR/Cas9-knockout HT29 cells lacking caspase-10 in addition to caspase-8 and RIPK3 or MLKL were resistant to IFNgamma/SM killing. Caspase-8 and RIPK1 deficiency was, however, sufficient to protect cells from IFNgamma/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. |