Original ClC-3 promotes paclitaxel resistance via modulating tubulins polymerization in ovarian cancer cells
Original ClC-3 promotes paclitaxel resistance via modulating tubulins polymerization in ovarian cancer cells
复制标题
ClC-3 通过调节卵巢癌细胞中微管蛋白聚合促进紫杉醇耐药
DOI：
10.1016/j.biopha.2021.111407
复制
发表时间：
2021-03-23
影响因子：
7.5
通讯作者：
Yang, Haifeng
中科院分区：
文献类型：
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作者：
Feng, Jiezhu;Peng, Zihan;Yang, Haifeng
上皮性卵巢癌是女性生殖系统疾病中死亡率较高的恶性肿瘤。紫杉醇（PTX）的获得性耐药是EOC的一线治疗之一，仍然是治疗的挑战。ClC-3是电压门控Cl-通道的成员，在多种细胞活动中起重要作用，包括化疗抗性。在这里，我们证明了与其亲本A2780细胞相比，ClC-3的蛋白表达和通道功能在PTX抗性A2780/PTX细胞中上调。siRNA沉默A2780/PTX细胞ClC-3表达后，细胞对PTX的敏感性部分恢复，恢复了G2/M期阻滞，氯通道恢复。C1 C-3 siRNA同时抑制C1 C-3和β-微管蛋白的表达，而β-微管蛋白siRNA仅降低C1 C-3自身的表达，而不影响C1 C-3的表达。C1 C-3 siRNA处理A2780/PTX细胞后，β-tubulin的聚合率增加，C1 C-3与β-tubulin之间存在蛋白质相互作用的可能性。总之，PTX耐药卵巢癌细胞中ClC-3蛋白的过表达促进了ClC-3与β-微管蛋白的结合，从而增加了β-微管蛋白游离形式的比例，减少了β-微管蛋白聚合形式的比例，最终降低了对PTX的敏感性。我们的研究结果阐明了ClC-3在调节PTX耐药中的新功能，ClC-3可能成为克服PTX耐药卵巢癌的潜在靶点。
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.