Cooperative TRAIL production mediates IFNα/Smac mimetic-induced cell death in TNFα-resistant solid cancer cells

Oncotarget
Stefanie RoeslerSimone Fulda

Abstract

Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFα as mediators of IFNα/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNα to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNα/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNα/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFα signaling by the TNFα scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNα/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNα/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5)...Continue Reading

References

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Citations

Jan 27, 2018·Cell Death & Disease·Simone Fulda
Apr 29, 2020·Cell Death and Differentiation·Najoua LalaouiJohn Silke
Dec 7, 2018·Journal of Cellular Biochemistry·Afshin NikkhooFarhad Jadidi-Niaragh

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Methods Mentioned

BETA
ubiquitination
flow cytometry
ELISA
PCR
Assay
Fluorescence-activated cell sorting

Software Mentioned

Origin
CalcuSyn
OriginLab

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