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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis
James E Vince1, W Wei-Lynn Wong, Nufail Khan
1Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia.
Cell
|November 21, 2007
Summary
IAP antagonists induce tumor cell death by activating NF-kappaB signaling and TNFalpha production, not just by inhibiting XIAP. Blocking this pathway allows tumor cells to survive, suggesting new cancer treatment strategies.
Area of Science:
- Molecular Biology
- Cancer Biology
- Immunology
Background:
- X-linked inhibitor of apoptosis protein (XIAP) is a key regulator of apoptosis.
- IAP antagonists (IACs) are designed to inhibit XIAP and induce tumor cell death.
- Previous understanding suggested IACs primarily target post-mitochondrial caspases.
Purpose of the Study:
- To investigate the mechanism of apoptosis induced by IAP antagonists.
- To determine the role of caspase 8 and NF-kappaB signaling in IAC-mediated cell death.
- To explore novel therapeutic applications of IACs in cancer treatment.
Main Methods:
- Treatment of tumor cells with IAP antagonists and caspase 8 inhibitors.
- Analysis of NF-kappaB signaling activation and TNFalpha production.
- Assessment of cell sensitivity to apoptosis induction.
Main Results:
- IAP antagonists induce apoptosis that is blocked by caspase 8 inhibitors, contrary to expectations.
- IACs activate NF-kappaB signaling through cIAP1 inhibition.
- NF-kappaB-stimulated TNFalpha production mediates autocrine tumor cell killing.
- Inhibition of NF-kappaB or TNFalpha rescues tumor cells from IAC-induced apoptosis.
- IAC treatment or cIAP1 deletion sensitizes cells to exogenous TNFalpha-induced apoptosis.
Conclusions:
- IAP antagonists induce cell death via a mechanism involving NF-kappaB and TNFalpha, not solely XIAP inhibition.
- Targeting NF-kappaB signaling or TNFalpha presents a potential strategy to overcome resistance to IACs.
- IACs may have novel therapeutic applications in combination with TNFalpha-based therapies for cancer treatment.
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