Autophagy and PERK-eIF2α pathway protect ovarian cancer cells from metformin-induced apoptosis

Abstract

Metformin, an oral biguanide for the treatment of type II diabetes, has been shown to have anticancer effect in ovarian cancer. Metformin induces starvation, causing endoplasmic reticulum (ER) stress and autophagy. The unfolded protein response (UPR) signaling by ER stress and autophagy acted as a survival or a death mechanism depending on types of malignancies. In this study, we found that metformin-induced apoptosis was relieved by autophagy and PERK/eIF2α pathway selectively in ovarian cancer cells, but not in normal cells, such as normal ovarian surface epithelial cells (OSE) and peripheral blood mononuclear cells (PBMC). Metformin induced autophagy, was verified by molecular markers, LC3B and ATG12-ATG5 for autophagosome formation at an early stage, and p62 along with increase of acidic vacuoles stained by acridine orange to detect degradation of the autophagosome at a late stage. Interestingly, metformin induced interdependent activation of autophagy and unfolded protein response (UPR), especially PERK/eIF2α pathway. Interaction of autophagy with PERK/eIF2α pathway played a protective role in ovarian cancer cells against metformin-induced apoptosis, demonstrated by assay using small molecular inhibitors. Finally, metformin with pharmacologic inhibitors had no effects on OSE and PBMC. In conclusion, these results suggest that inhibition of interaction between autophagy and PERK could enhance selective anticancer effect of metformin in ovarian cancer cells.