Autophagy as a survival response to sigma receptor ligand‐induced endoplasmic reticulum stress

Abstract

The sigma1 receptor is a novel endoplasmic reticulum (ER) molecular chaperone that is highly expressed in certain tumor cell types. Small molecule ligands targeting sigma1 inhibit cell proliferation and induce apoptosis in vitro and inhibit tumor growth in vivo. However, the cellular pathways engaged by sigma1 receptor‐ligand interaction are not well defined. We previously observed that treatment with sigma1 antagonists activates autophagy. Here, we elucidate the events leading to this activation. Autophagy can function as a death or survival pathway in response to cell stress. As sigma1 is enriched in the ER, we asked if sigma1 ligand treatment induces ER stress. We found that sigma antagonists induce ER stress and activate the unfolded protein response (UPR) in a dose and time responsive manner. We then asked if autophagy functions as a death or survival pathway. We found that UPR activation precedes autophagosome formation and autophagy precedes apoptosis in antagonist‐treated cells. Furthermore, inhibition of autophagosome formation and degradation accelerates antagonist‐mediated apoptosis. Together, these data suggest that autophagy is a survival response to sigma antagonist‐induced ER stress.