Department of Pharmacology, Medical College, Jinan University, Guangzhou 510632, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Biomed Pharmacother. 2021 Jun;138:111407. doi: 10.1016/j.biopha.2021.111407. Epub 2021 Mar 23.
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 β-tubulin, whereas the β-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 β-tubulin, and the possibility of proteins interaction between ClC-3 and β-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 β-tubulin, which in turn increase the ration of free form and decrease the quota of the polymeric form of β-tubulin, and finally reduce the sensitivity to PTX. Our findings elucidated a novel function of ClC-3 in regulating PTX resistance and ClC-3 could serve as a potential target to overcome the PTX resistance ovarian cancer.
上皮性卵巢癌（EOC）是女性生殖系统疾病中恶性程度高、死亡率高的肿瘤。获得性对紫杉醇（PTX）的耐药性仍然是治疗的挑战。ClC-3 是电压门控 Cl 通道的成员之一，在多种细胞活动中发挥着重要作用，包括化疗耐药性。在这里，我们证明与亲本 A2780 细胞相比，PTX 耐药 A2780/PTX 细胞中 ClC-3 的蛋白表达和通道功能上调。用 siRNA 沉默 A2780/PTX 细胞中的 ClC-3 表达部分恢复了 PTX 敏感性，通过恢复 G2/M 期阻滞和恢复氯离子通道阻断来实现。ClC-3 siRNA 既能抑制 ClC-3 的表达，又能抑制 β-微管蛋白的表达，而 β-微管蛋白 siRNA 只能降低自身的表达，而不影响 ClC-3 的表达。此外，用 ClC-3 siRNA 处理 A2780/PTX 细胞增加了 β-微管蛋白的聚合比例，并且 ClC-3 和 β-微管蛋白之间存在蛋白质相互作用的可能性。总之，ClC-3 蛋白在上皮性卵巢癌耐药细胞中的过度表达促进了 ClC-3 和 β-微管蛋白的结合，进而增加了自由形式的比例，降低了聚合形式的β-微管蛋白的配额，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 耐药性中的新功能，ClC-3 可以作为克服 PTX 耐药性卵巢癌的潜在靶点。
