The anti-malarial chloroquine suppresses proliferation and overcomes cisplatin resistance of endometrial cancer cells via autophagy inhibition

• Chloroquine attenuated proliferation and induced apoptosis in endometrial cancer cells in part via autophagy inhibition.
• Autophagy inhibition by either chloroquine or knockdown of ATG5/7 improved cisplatin-sensitivity in Ishikawa endometrial cancer cells.
• Cisplatin-resistant Ishikawa cells, with an increased basal level of autophagy, were more sensitive to chloroquine than parental cells.

ObjectiveThe anti-malarial drug chloroquine (CQ) is also known as an autophagy inhibitor. Autophagy can promote tumor growth by fueling the necessary energy metabolism and inducing resistance to chemotherapy and/or irradiation in various human cancers. However, the role of autophagy in endometrial cancer has not yet been established. We investigated the anti-tumor effects and autophagy inhibition caused by CQ in endometrial cancer cells.MethodsCell proliferation and cell cycle were assessed in response to CQ in six endometrial cancer cell lines by using an MTT assay and/or flow cytometry. To assess the level of autophagy, western blotting and an immunofluorescence assay were used to measure LC3 expression. The effects of knockdown of either ATG5 or ATG7, both of which are indispensable for induction of autophagy, were assessed via an MTT assay. Sensitivity to CQ was compared between parental and cisplatin-resistant (CP-r) Ishikawa endometrial cancer cells.ResultsCQ suppressed proliferation in all six endometrial cancer cell lines in a dose-dependent manner, whereas it increased the population of apoptotic cells. Inhibition of autophagy via knockdown of either ATG5 or ATG7 decreased the sensitivity to CQ. Additionally, sensitivity to cisplatin was improved by knocking down ATG5 or ATG7. Finally, CP-r Ishikawa cells, with a high basal level of autophagy, were more sensitive to CQ than parental Ishikawa cells.ConclusionsOur data suggest that autophagy is involved in endometrial tumor growth and cisplatin resistance. Furthermore, our data support a therapeutic role for CQ in endometrial cancer cells with upregulation of autophagy.