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, chemo-resistance 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 tumors, while its role in the chemotherapy of cholangiocarcinoma (CCA) is still poorly understood. Herein, we observed that ClC-3 was highly expressed in CCA chemo-resistant 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.

SOX2 regulates paclitaxel resistance of A549 non‑small cell lung cancer cells via promoting transcription of ClC‑3

“…Accumulating studies have suggested that ClC-3 is expressed in a number of cancer cells and serves a well-defined role in cell proliferation, apoptosis and metastasis (12)(13)(14)(15). Furthermore, abnormality of ClC-3 expression has been demonstrated to be associated with the development of drug resistance, including PTX, cisplatin and etoposide resistance, in various tumor cells (16)(17)(18)(19). However, the potential regulatory mechanism of ClC-3 in PTX resistance of NSCLC remains largely unknown.…”

Supramolecular nanoprodrug based on a chloride channel blocker and glycosylated pillar[5]arenes for targeted chemoresistance cancer therapy

“…Common ion channels include cation channels (potassium-, calcium-, and sodium-ion channels) as well as the most important anion channel, for chloride ions. 10,11 Among them, the chloride channel (TMEM16A) is involved in many malignancies, where it is not only overexpressed but may also induce drug resistance. 12 To the best of our knowledge, blocking chloride channels to inhibit chemoresistance for enhancing the efficacy of chemotherapy has not yet been reported.…”