RT Journal Article
SR Electronic
T1 Sequential Cytoprotective Responses to Sigma1 Ligand–Induced Endoplasmic Reticulum Stress
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 751
OP 762
DO 10.1124/mol.113.087809
VO 84
IS 5
A1 Joel M. Schrock
A1 Christina M. Spino
A1 Charles G. Longen
A1 Stacy M. Stabler
A1 Jacqueline C. Marino
A1 Gavril W. Pasternak
A1 Felix J. Kim
YR 2013
UL http://molpharm.aspetjournals.org/content/84/5/751.abstract
AB 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 Sigma1mediated. We find that UPR activation precedes autophagosome formation and autophagy precedes apoptosis in Sigma1 ligand-treated 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.