Blockade of chloride channel-3 enhances cisplatin sensitivity of cholangiocarcinoma cells though inhibiting autophagy.

ABSTRACT

Chemotherapy is one of the most important strategies in the treatment of cancer; however, chemoresistance restricts the effect of chemotherapy. Growing reports suggest that chloride channel-3 (ClC-3) is involved in regulating the sensitivity of multiple chemotherapeutic agents in the chemotherapy of various tumours, while its role in the chemotherapy of cholangiocarcinoma (CCA) is still poorly understood. Herein, we observed that ClC-3 was highly expressed in CCA chemoresistant tissues and CCA cisplatin-resistant cells QBC939/DDP, and the sensitivities of QBC939 and QBC939/DDP cells to cisplatin were all increased after inhibition of ClC-3. Further mechanism exploration revealed that ClC-3 knockdown reduced the level of autophagy. Furthermore, in both QBC939 and QBC939/DDP cells, the autophagy agonist rapamycin eliminated the increased cisplatin sensitivity of ClC-3 knockdown without affecting ClC-3 expression. Collectively, all the findings demonstrate that ClC-3 knockdown increases cisplatin-induced cell death in CCA cells though inhibiting autophagy, regardless of the occurrence of cisplatin resistance. In addition, our results also suggest that targeted inhibition of ClC-3 may be a potential strategy for chemosensitization in CCA chemotherapy.