Gene & Cell Therapy Team, Division of Drug Development & Optimization, New Drug Development Center, Osong Medical Innovation Foundation, Osongsaengmyung-ro 123, Osong-eup, Heungdeok-gu, Cheongju-si, Chungbuk 28160, Korea.
Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea.
Int J Mol Sci. 2020 Mar 2;21(5):1710. doi: 10.3390/ijms21051710.
Tumor cell resistance to anti-cancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin in T24R2 cells, a T24-derived cell line. Treatment with cordycepin or cisplatin (2 μg/mL) alone failed to induce cell death in T24R2 cells, but combination treatment with these drugs significantly induced apoptosis through mitochondrial pathways, including depolarization of mitochondrial membranes, decrease in anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, and increase in pro-apoptotic proteins Bak and Bax. High expression levels of MDR1 were the cause of cisplatin resistance in T24R2 cells, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on transcription factor Ets-1 in T24R2 cells. Although correlation exists between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr38 phosphorylated form (pThr38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 levels and reduced MDR1 transcription, probably through its effects on PI3K signaling, inducing the resensitization of T24R2 cells to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of cancer in patients with resistance to anti-cancer drugs.
肿瘤细胞对抗癌药物的耐药性是肿瘤治疗的主要障碍。在这项研究中，我们研究了蛹虫草素介导的 T24 衍生细胞系 T24R2 细胞对顺铂再敏化的机制。蛹虫草素或顺铂（2μg/ml）单独处理不能诱导 T24R2 细胞死亡，但这些药物联合治疗通过线粒体途径显著诱导细胞凋亡，包括线粒体膜去极化、抗凋亡蛋白 Bcl-2、Bcl-xL 和 Mcl-1 减少以及促凋亡蛋白 Bak 和 Bax 增加。MDR1 的高表达是 T24R2 细胞对顺铂耐药的原因，蛹虫草素通过抑制 MDR1 启动子活性显著降低 MDR1 的表达。MDR1 启动子活性依赖于 T24R2 细胞中的转录因子 Ets-1。虽然膀胱癌患者中 MDR1 和 Ets-1 表达之间存在相关性，但活性 Ets-1（Thr38 磷酸化形式，pThr38）是诱导 MDR1 表达的关键。蛹虫草素降低 pThr-38 Ets-1 水平并减少 MDR1 转录，可能是通过其对 PI3K 信号的影响，诱导 T24R2 细胞对顺铂的再敏化。结果表明，蛹虫草素有效地使顺铂耐药的膀胱癌细胞对顺铂再敏化，因此可能成为治疗对抗癌药物耐药的癌症患者的一种策略。
