SMAC mimetics are a new class of targeted drugs being developed for the treatment of solid tumours and hematologic cancers. SMAC mimetics are inhibitors of a family of cellular proteins called the Inhibitor of Apoptosis Proteins (IAPs). The goal of SMAC mimetics is to suppress the IAPs, reestablishing the apoptotic pathways and inducing cancer cell death. The unique action of SMAC mimetics can also enhance the therapeutic activity of many existing cancer therapies

Nicole and Simone have published 2 papers that investigate the use of SMAC mimetics in combination with ER stress inducing agents.The first paper demonstrates that SMAC mimetic can suppress tunicamycin-induced apoptosis via resolution of ER stress while the second paper demonstrates that NF-κB plays a role in SMAC mimetic-conferred protection from ER stress induced apoptosis.

Therefore these papers together demonstrate that Smac mimetics suppress TM-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress in addition to the contribution of canonical and non-canonical NF-κB signalling.

 

 

 

 

 

Smac mimetic suppresses tunicamycin-induced apoptosis via resolution of ER stress.

Behnaz Ahangarian Abhari*, Nicole McCarthy*, Marie Le Berre, Michelle Kilcoyne, Lokesh Joshi,

Patrizia Agostinis and Simone Fulda, March 2019, Cell Death and Disease

Available from: https://www.nature.com/articles/s41419-019-1381-z

 

NF-κB contributes to Smac mimetic-conferred protection from tunicamycin-induced apoptosis.

Abhari BA, McCarthy N, Agostinis P, Fulda S., Januray 2019, Apoptosis

Available from: https://www.ncbi.nlm.nih.gov/pubmed/30680482

 

Summary

Tunicamycin (TM) is a typical ER stress inducer that blocks N-linked glycosylation and can be used to induce cell death. Smac mimetics (inhibit Inhibitor of Apoptosis proteins (IAP)), c

an also be used to induce cell death. Nicole and colleagues discovered that, surprisingly, the combination of TM and Smac mimetics results in a rescue in cell death in a number of cancer entities suggesting an anti-apoptotic effect of smac mimetics on TM induced cell death.  In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin, dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). BV6 abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment.

Smac mimetics have been shown to activate Nuclear Factor-kappa B (NF-κB). BV6-stimulated activation of NF-κB contributes to this resolution of ER stress, since NF-κB inhibition reversed the BV6-imposed protection against TM and counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6.

These studies are the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics and how NF-κB activation by Smac mimetic contributes to this protection against TM-induced apoptosis