Original ClC-3 promotes paclitaxel resistance via modulating tubulins polymerization in ovarian cancer cells

Epithelial ovarian cancers (EOC) present as malignant tumors with high mortality in the female reproductive system diseases. Acquired resistance to paclitaxel (PTX), one of the first-line treatment of EOC, remains a therapeutic challenge. ClC-3, a member of the voltage-gated Cl- channels, plays an essential role in a variety of cellular activities, including chemotherapeutic resistance. Here, we demonstrated that the protein expression and channel function of ClC-3 was upregulated in PTX resistance A2780/PTX cells compared with its parental A2780 cells. The silence of ClC-3 expression by siRNA in A2780/PTX cells partly recovered the PTX sensitivity through restored the G2/M arrest and resumed the chloride channel blocked. ClC-3 siRNA both inhibited the expression of ClC-3 and beta-tubulin, whereas the beta-tubulin siRNA reduced the expression of itself only, without affecting the expression of ClC-3. Moreover, treatment of ClC-3 siRNA in A2780/PTX cells increased the polymerization ratio of beta-tubulin, and the possibility of proteins interaction between ClC-3 and beta-tubulin was existing. Take together, the over-expression of ClC-3 protein in PTX-resistance ovarian cancer cells promotes the combination of ClC-3 and beta-tubulin, which in turn increase the ration of free form and decrease the quota of the polymeric form of beta-tubulin, and finally reduce the sensitivity to PTX. Our findings elucidated a novel function of ClC-3 in regu-lating PTX resistance and ClC-3 could serve as a potential target to overcome the PTX resistance ovarian cancer.

Automated summary

Over-expression of ClC-3 protein in PTX-resistant ovarian cancer cells promotes the combination of ClC-3 and beta-tubulin, reducing sensitivity to PTX.