Sequential cytoprotective responses to Sigma1 ligand-induced endoplasmic reticulum stress Journal Article


Authors: Schrock, J. M.; Spino, C. M.; Longen, C. G.; Stabler, S. M.; Marino, J. C.; Pasternak, G. W.; Kim, F. J.
Article Title: Sequential cytoprotective responses to Sigma1 ligand-induced endoplasmic reticulum stress
Abstract: The Sigma1 receptor (Sigma1) is an endoplasmic reticulum (ER) integral membrane protein that is highly expressed in a number of cancer cell lines. Small molecule compounds targeting Sigma1 (Sigma1 ligands) inhibit cancer cell proliferation and induce apoptotic cell death in vitro and inhibit tumor growth in xenograft experiments. However, the cellular pathways activated by Sigma1 protein-ligand interaction are not well defined. Here, we find that treatment with some Sigma1 ligands induces ER stress and activates the unfolded protein response (UPR) in a dose- and time-responsive manner in a range of adenocarcinoma cell lines. Autophagy is engaged after extended treatment with Sigma1 ligands, which suggests that protracted UPR results in autophagy as a secondary response. Inhibition of UPR by RNAi-mediated knockdown of inositol-requiring enzyme 1α and activating transcription factor 4 abrogates autophagosome formation, as does knockdown of essential autophagy gene products Beclin1 and autophagy protein 5. Knockdown of Sigma1 also suppresses IPAG [1-(4-iodophenyl)-3-(2-adamantyl) guanidine] induced UPR marker and autophagosome levels, indicating that this response is indeed Sigma1-mediated. We find that UPR activation precedes autophagosome formation and autophagy precedes apoptosis in Sigma1 ligandtreated cells. These processes are reversible, and washout of IPAG before cell death results in a return of autophagosomes and UPR markers toward basal levels. However, inhibition of Sigma1 ligand-induced UPR or autophagy accelerates apoptotic cell death. Together, these data suggest that UPR and autophagy are engaged as primary and secondary cytoprotective responses, respectively, to Sigma1 ligand-induced disruption of cancer cell protein homeostasis. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Keywords: controlled study; protein expression; unclassified drug; human cell; protein function; adenocarcinoma; cell proliferation; cell death; apoptosis; protein metabolism; haloperidol; rna interference; cancer cell; tumor cell line; protein induction; autophagy; cell protection; activating transcription factor 4; inositol; mediator; unfolded protein response; n allylnormetazocine; pentazocine; sigma 1 opiate receptor; autophagosome; beclin 1; guanidine derivative; endoplasmic reticulum stress; autophagy protein 5; 1 ( 4 iodophenyl) 3 ( 2 adamantyl)guanidine; 1 phenylcyclohexanecarboxylic acid 2 morpholinoethyl ester; inositol requiring enzyme 1alpha
Journal Title: Molecular Pharmacology
Volume: 84
Issue: 5
ISSN: 0026-895X
Publisher: The American Society for Pharmacology and Experimental Therapeutics  
Date Published: 2013-11-01
Start Page: 751
End Page: 762
Language: English
DOI: 10.1124/mol.113.087809
PROVIDER: scopus
PMCID: PMC3807076
PUBMED: 24006496
DOI/URL:
Notes: --- - "Export Date: 2 December 2013" - "CODEN: MOPMA" - "Source: Scopus"
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MSK Authors
  1. Gavril W Pasternak
    296 Pasternak