Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
J Cell Physiol. 2020 Dec;235(12):9589-9600. doi: 10.1002/jcp.29767. Epub 2020 May 5.
Cisplatin is a widely used platinum-based anticancer drug in the chemotherapy of numerous human cancers. However, cancer cells acquire resistance to cisplatin. So far, functional loss of volume-sensitive outwardly rectifying (VSOR) Cl channels has been reported to contribute to cisplatin resistance of cancer cells. Here, we analyzed protein expression patterns of human epidermoid carcinoma KB cells and its cisplatin-resistant KCP-4 cells. Intriguingly, KB cells exhibited higher β-actin expression and clearer actin filaments than KCP-4 cells. The β-actin knockdown in KB cells decreased VSOR Cl currents and inhibited the regulatory volume decrease (RVD) process after cell swelling. Consistently, KB cells treated with cytochalasin D, which depolymerizes actin filaments, showed smaller VSOR Cl currents and slower RVD. Cytochalasin D also inhibited cisplatin-triggered apoptosis in KB cells. These results suggest that the disruption of actin filaments cause the dysfunction of VSOR Cl channels, which elicits resistance to cisplatin in human epidermoid carcinoma cells.
顺铂是一种广泛应用于多种人类癌症化疗的含铂抗癌药物。然而，癌细胞会对顺铂产生耐药性。到目前为止，已有研究报道，体积敏感性外向整流 (VSOR) Cl 通道功能丧失有助于癌细胞对顺铂产生耐药性。在这里，我们分析了人表皮样癌细胞 KB 及其顺铂耐药细胞 KCP-4 的蛋白表达模式。有趣的是，KB 细胞的 β-肌动蛋白表达水平更高，肌动蛋白丝也更清晰。KB 细胞中的 β-肌动蛋白敲低会降低 VSOR Cl 电流，并抑制细胞肿胀后的调节性体积减少 (RVD) 过程。同样，用细胞松弛素 D 处理 KB 细胞，后者会破坏肌动蛋白丝，导致 VSOR Cl 电流减小，RVD 减慢。细胞松弛素 D 还抑制了 KB 细胞中顺铂触发的细胞凋亡。这些结果表明，肌动蛋白丝的破坏导致 VSOR Cl 通道功能障碍，从而引发人表皮样癌细胞对顺铂的耐药性。
