Smac mimetic suppresses tunicamycin-induced apoptosis via resolution of ER stress.
Apoptosis
/ drug effects
Apoptosis Regulatory Proteins
/ chemistry
Cell Line, Tumor
Cell Survival
/ drug effects
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress
/ drug effects
Gene Knockdown Techniques
Glycosylation
/ drug effects
HEK293 Cells
Heat-Shock Proteins
/ metabolism
Humans
Inhibitor of Apoptosis Proteins
/ genetics
Mitochondrial Proteins
/ chemistry
Molecular Mimicry
NF-kappa B
/ metabolism
Neuroblastoma
Oligopeptides
/ pharmacology
Protective Agents
/ pharmacology
Transcription Factor CHOP
/ metabolism
Transduction, Genetic
Tunicamycin
/ pharmacology
Unfolded Protein Response
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
15 02 2019
15 02 2019
Historique:
received:
24
11
2017
accepted:
19
12
2018
revised:
02
12
2018
entrez:
17
2
2019
pubmed:
17
2
2019
medline:
9
4
2020
Statut:
epublish
Résumé
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently 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. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is 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.
Identifiants
pubmed: 30770792
doi: 10.1038/s41419-019-1381-z
pii: 10.1038/s41419-019-1381-z
pmc: PMC6377606
doi:
Substances chimiques
Apoptosis Regulatory Proteins
0
BV6 peptide
0
DDIT3 protein, human
0
DIABLO protein, human
0
Endoplasmic Reticulum Chaperone BiP
0
HSPA5 protein, human
0
Heat-Shock Proteins
0
Inhibitor of Apoptosis Proteins
0
Mitochondrial Proteins
0
NF-kappa B
0
Oligopeptides
0
Protective Agents
0
Tunicamycin
11089-65-9
Transcription Factor CHOP
147336-12-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
155Commentaires et corrections
Type : ErratumIn
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