Role of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma.

Abstract

Endoplasmic reticulum (ER) is an essential site of cellular homeostasis regulation. ER stress (ERS) may induce autophagy in tumor cells that escape from apoptosis. The present study examined the effects and mechanism of ERS on cisplatin (DDP) sensitivity in ovarian carcinoma. SKOV3 tumor cells treated with Saquinavir were subjected to western blot and reverse transcription-quantitative polymerase chain reaction analysis to determine protein and messenger RNA (mRNA) expression levels of mechanistic target of rapamycin (mTOR) and Beclin 1. MTT assay was used to analyze the influence of Saquinavir on DDP resistance in SKOV3 cells. Saquinavir induced glucose-regulated protein 78 expression, which is a marker of ERS. Following treatment with various doses of Saquinavir, the sensitivity of ovarian cancer cells to DDP decreased significantly. Protein and mRNA expression levels of mTOR and Beclin 1 in SKOV3 cells were increased when the cells were exposed to Saquinavir or DDP for 24 h. Moreover, mTOR and Beclin 1 expression levels were highest in the Saquinavir + DDP group (0.684±0.072 and 0.6467±0.0468, respectively). SKOV3 tumor cells were also exposed to the autophagy inhibitor, 3-methyladenine (3-MA), and different concentrations of Saquinavir. Analysis of half maximal inhibitory concentration (IC50) values of DDP after this treatment demonstrated that IC50 values were significantly decreased compared with Saquinavir alone (P<0.001), suggesting that the sensitivity to DDP was improved in ovarian cancer cells after 3-MA exposure. These findings demonstrated that Saquinavir is able to induce ERS in SKOV3 cells effectively, and ER-induced stress may decrease the sensitivity of DDP in SKOV3 cells. Furthermore, ERS may regulate cell autophagy through the mTOR and Beclin 1 pathways, leading to a reduction in the sensitivity of DDP in SKOV3 cells. ERS in tumor cells and autophagy may be a potential target to improve the therapeutic effect of chemotherapy and reduce drug resistance in tumors.