PT  - JOURNAL ARTICLE
AU  - Joel M Schrock
AU  - Christina M Spino
AU  - Charles G Longen
AU  - Stacy M Stabler
AU  - Jacqueline C Marino
AU  - Gavril W Pasternak
AU  - Felix J Kim
TI  - Sequential Cytoprotective Responses to Sigma1 Ligand Induced Endoplasmic Reticulum Stress
AID  - 10.1124/mol.113.087809
DP  - 2013 Sep 04
TA  - Molecular Pharmacology
PG  - mol.113.087809
4099  - http://molpharm.aspetjournals.org/content/early/2013/09/04/mol.113.087809.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/09/04/mol.113.087809.full
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 following extended treatment with Sigma1 ligands, suggesting that protracted UPR results in autophagy as a secondary response. Inhibition of UPR by RNAi mediated knockdown of IRE1α and ATF4 abrogates autophagosome formation, as does knockdown of essential autophagy gene products Beclin1 and ATG5. Knockdown of Sigma1 also suppresses IPAG 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 ligand treated cells. These processes are reversible, and wash-out of IPAG prior to 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.