ClC5 is upregulated in paclitaxel resistant breast cancer cells and decreases paclitaxel sensitivity via promoting HMGB1 translocation

The resistance of cancer cells to chemotherapy largely restricts the effective treatment of cancer. Chloride ions transport proteins or channel proteins are closely related with hallmarks of cancer, including unlimited proliferation, cell death resistance and metastasis. The present study was to investigate the effects of ClC-5, a member of voltage-gated chloride channels, on paclitaxel-induced chemoresistance and identify the underlying mechanisms of the action of ClC-5 in breast cancer cell line MCF-7 cells. We firstly established in vitro MCF-7 cells and paclitaxel-resistant MCF-7/PTX cells as cell model with IC50 of 4.78 and 11.92 mu M, respectively. Interestingly, we found that ClC-5 expression was dramatically increased in MCF-7/PTX cells compared with in parental cells. Moreover, knockdown of ClC-5 with siRNA further enhanced paclitaxel-induced cell growth inhibition and apoptosis, accompanied by reduced Bcl-2 expression and increased Bax expression. However, overexpression of ClC-5 with adenovirus had opposite results. Additionally, we also found higher expression of high-mobility group box 1 (HMGB1) in MCF-7/PTX cells than in MCF-7 cells. With the increasing concentrations of paclitaxel, HMGB1 was gradually translocated from nucleus to cytoplasm in MCF-7 cells, and this translocation was significantly enhanced by ClC-5 overexpression. Furthermore, inference with endogenous HMGB1 almost abolished the inhibitory effects of ClC-5 overexpression on paclitaxel-induced apoptosis in MCF-7 cells. In conclusion, our data indicate that ClC-5 expression may be a potential mechanism underlying paclitaxel resistance in breast cancer, and inhibition of ClC-5 could improve the efficiency of paclitaxel in the induction of apoptosis.