PMID- 30770792
OWN - NLM
STAT- MEDLINE
DCOM- 20200406
LR  - 20211204
IS  - 2041-4889 (Electronic)
VI  - 10
IP  - 3
DP  - 2019 Feb 15
TI  - Smac mimetic suppresses tunicamycin-induced apoptosis via resolution of ER 
      stress.
PG  - 155
LID - 10.1038/s41419-019-1381-z [doi]
LID - 155
AB  - 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-kappaB (NF-kappaB) contributes to the resolution of ER 
      stress, since NF-kappaB inhibition by overexpression of dominant-negative IkappaBalpha 
      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.
FAU - Abhari, Behnaz Ahangarian
AU  - Abhari BA
AD  - Institute for Experimental Cancer Research in Pediatrics, Goethe-University 
      Frankfurt, Komturstrasse 3a, 60528, Frankfurt, Germany.
FAU - McCarthy, Nicole
AU  - McCarthy N
AD  - Institute for Experimental Cancer Research in Pediatrics, Goethe-University 
      Frankfurt, Komturstrasse 3a, 60528, Frankfurt, Germany.
FAU - Le Berre, Marie
AU  - Le Berre M
AD  - Glycoscience Group, National University of Ireland, Galway, Ireland.
FAU - Kilcoyne, Michelle
AU  - Kilcoyne M
AUID- ORCID: 0000-0002-8870-1308
AD  - Glycoscience Group, National University of Ireland, Galway, Ireland.
FAU - Joshi, Lokesh
AU  - Joshi L
AD  - Glycoscience Group, National University of Ireland, Galway, Ireland.
FAU - Agostinis, Patrizia
AU  - Agostinis P
AD  - Cell Death Research and Therapy Unit, Department of Cellular and Molecular 
      Medicine, KU Leuven, 3000, Leuven, Belgium.
FAU - Fulda, Simone
AU  - Fulda S
AUID- ORCID: 0000-0002-0459-6417
AD  - Institute for Experimental Cancer Research in Pediatrics, Goethe-University 
      Frankfurt, Komturstrasse 3a, 60528, Frankfurt, Germany. simone.fulda@kgu.de.
AD  - German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany. 
      simone.fulda@kgu.de.
AD  - German Cancer Research Center (DKFZ), Heidelberg, Germany. simone.fulda@kgu.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190215
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BV6 peptide)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (DIABLO protein, human)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Oligopeptides)
RN  - 0 (Protective Agents)
RN  - 11089-65-9 (Tunicamycin)
RN  - 147336-12-7 (Transcription Factor CHOP)
SB  - IM
EIN - Cell Death Dis. 2020 Sep 25;11(9):806. PMID: 32978371
MH  - Apoptosis/*drug effects
MH  - Apoptosis Regulatory Proteins/chemistry
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Gene Knockdown Techniques
MH  - Glycosylation/drug effects
MH  - HEK293 Cells
MH  - Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins/genetics
MH  - Mitochondrial Proteins/chemistry
MH  - Molecular Mimicry
MH  - NF-kappa B/metabolism
MH  - Neuroblastoma
MH  - Oligopeptides/*pharmacology
MH  - Protective Agents/*pharmacology
MH  - Transcription Factor CHOP/metabolism
MH  - Transduction, Genetic
MH  - Tunicamycin/*pharmacology
MH  - Unfolded Protein Response
PMC - PMC6377606
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/02/17 06:00
MHDA- 2020/04/09 06:00
PMCR- 2019/02/15
CRDT- 2019/02/17 06:00
PHST- 2017/11/24 00:00 [received]
PHST- 2018/12/19 00:00 [accepted]
PHST- 2018/12/02 00:00 [revised]
PHST- 2019/02/17 06:00 [entrez]
PHST- 2019/02/17 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/02/15 00:00 [pmc-release]
AID - 10.1038/s41419-019-1381-z [pii]
AID - 1381 [pii]
AID - 10.1038/s41419-019-1381-z [doi]
PST - epublish
SO  - Cell Death Dis. 2019 Feb 15;10(3):155. doi: 10.1038/s41419-019-1381-z.