Induction of autophagy contributes to cisplatin resistance in human ovarian cancer cells

Abstract

Cisplatin resistance is a major challenge in the clinical treatment of ovarian cancer, of which the underlying mechanisms remain unknown. The aim of the present study was to explore the role of autophagy in cisplatin resistance in ovarian cancer cells. A2780cp cisplatin-resistant ovarian carcinoma cells and the A2780 parental cell line, were used as a model throughout the present study. The cell viability was determined using a water soluble tetrazolium salt-8 assay, and western blot analysis was performed to determine the protein expression levels of microtubule-associated protein 1 light chain 3 (LC3 I and LC3 II), and Beclin 1. Beclin 1 small interfering (si)RNA and 3-methyladenine (3-MA) were used to determine whether inhibition of autophagy may re-sensitize cisplatin-resistant cells to cisplatin. The ultrastructural analysis of autophagosomes was performed using transmission electron microscopy, and apoptosis was measured by flow cytometry. In both A2780cp and A2780 cells, cisplatin induced the formation of autophagosomes and upregulated the expression levels of autophagy protein markers, LC3 II and Beclin 1. However, the levels of autophagy were significantly higher in A2780cp cells, as compared with the A2780 cells. The combined treatment of cisplatin with 3-MA, the autophagy pharmacological inhibitor, increased the cell death rate, but had no effects on apoptosis, as compared with cisplatin treatment alone in A2780cp cells. However, inhibition of autophagy by siRNA knockdown of Beclin 1 expression enhanced cisplatin-induced cell death and apoptosis. The findings of the present study suggest that autophagy has a protective role in human ovarian cancer cells, and that targeting autophagy may promote chemotherapeutic sensitivity.

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

“…S3C), which was consistent with a previous report. 47 These results demonstrated a complicated regulatory network including autophagy, which is utilized by cancer cells to overcome survival stress and achieve drug resistance.…”

“…Indeed, cisplatin induced protective autophagy in resistance cells and inhibition of autophagy by small molecules such as CQ could significantly sensitize cisplatin-induced apoptosis. 47 Therefore, targeting autophagy may be a potential therapeutic strategy in cancer treatment, especially in drug-resistant cancer, where anticancer agent-induced autophagy exerted a protective function.…”

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

“…However, acquired resistance to cisplatin remains a major limitation of its success clinically in ovarian cancer. Increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy, however, the underlying mechanisms have not been fully elucidated (8)(9)(10)(11).…”

Platinum-resistance and AKT Over-expression in Ovarian Cancer

“…The cisplatinum-resistant A2780cis cell line has been developed by chronic exposure of the parental cisplatinum-sensitive A2780 cell line to increasing concentrations of the chemotherapeutic agent [94]. These cell lines are excellent models for analyzing the molecular basis for cisplatinum resistance in ovarian cancer [72][73][74][95][96][97][98]. According to these studies AKT over-expression in ovarian cancer is at least one important reason for platinum resistance in this tumour entity [61,72,99].…”