Role of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma

Abstract

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 (IC 50 ) values of DDP after this treatment demonstrated that IC 50 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.

2‐Deoxy‐D‐glucose has distinct and cell line‐specific effects on the survival of different cancer cells upon antitumor drug treatment

“…This emphasize on the different outcomes of ER stress in different experimental systems. At the same time, dose‐dependent stimulation of ER stress and subsequent autophagy may significantly suppress apoptosis . Certainly, stimulation of autophagy by 2‐DG in cisplatin‐treated HCT116 cells attenuated the apoptotic response.…”

Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway

“…Activating ERS has attracted a great deal of attention for cancer therapy due to the fact that ERS can effectively enhance tumor cell apoptosis [16]. ERS can decrease cisplatin sensitivity to ovarian carcinoma cells by regulating cell autophagy via the pathways of mTOR and Beclin1 [17]. Chen et al demonstrated that cxc195 and ERS induced apoptosis, inhibited phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway in HepG2 cells [18].…”

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

“…Expression of ER stress markers such as GRP78 is increased in tissue specimens from endometrioid endometrial carcinomas at both mRNA and protein levels 20 . In addition, levels of GRP78 could affect the sensitivity to cisplatin by regulating autophagy and apoptosis in EOC [21][22][23] and may be involved in EOC resistance to platinum-based therapy 24 . Like GRP78, PDI also has a dual role in cell death and survival during ER stress.…”