Twist Confers Chemoresistance to Anthracyclines in Bladder Cancer through Upregulating P-Glycoprotein
Twist Confers Chemoresistance to Anthracyclines in Bladder Cancer through Upregulating P-Glycoprotein
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Twist 通过上调 P-糖蛋白赋予膀胱癌蒽环类药物化疗耐药性
DOI：
10.1159/000341860
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发表时间：
2012-01-01
期刊：
影响因子：
3.3
通讯作者：
He, Dalin
中科院分区：
文献类型：
--
作者：
Chen, Yule;Li, Lei;He, Dalin
背景：膜转运蛋白 P-糖蛋白（P-gp）被发现可介导化疗耐药性，这是多种人类癌症中有效化疗的障碍之一。据报道，转录因子 Twist 参与癌症侵袭和转移，在化疗耐药的进展中也发挥着至关重要的作用。然而，Twist 对 P-gp 相关化疗耐药性的影响仍然值得怀疑。方法和结果：我们发现 Twist 可以调节 P-gp 的表达，从而赋予人膀胱癌细胞对蒽环类药物的耐药性。首先，Twist被发现与人膀胱癌细胞和组织中的P-gp共表达，这与蒽环类药物的化疗耐药性增强有关。其次，通过特异性 siRNA 治疗敲除 Twist，通过抑制 P-gp 表达，使膀胱癌细胞对蒽环类药物显着敏感。与未处理的细胞相比，短暂接触蒽环类药物后存活的膀胱癌细胞表现出更高水平的 P-gp 表达和更多的 Twist 核定位。结论：我们报告了膀胱癌蒽环类化疗耐药的新机制，其中激活的 Twist 除了具有抗凋亡作用之外还介导 P-gp 表达。针对 Twist 的治疗策略可能会改善化疗后复发性膀胱癌的治疗。
Background: The membrane transporter P-glycoprotein (P-gp) was found to mediate chemoresistance, which is one of the obstacles to effective chemotherapy in several types of human cancer. The transcription factor Twist, which has been reported to participate in cancer invasion and metastasis, also plays a vital role in the progression of chemoresistance. However, the effect of Twist on P-gp-related chemoresistance remains dubious. Methods and Results: We found that Twist can regulate the expression of P-gp and then confer resistance to anthracycline drugs in human bladder cancer cells. Firstly, Twist was found to be coexpressed with P-gp in human bladder cancer cells and tissues, which were associated with enhanced chemoresistance to anthracycline drugs. Secondly, knockdown of Twist by specific siRNA treatment significantly sensitized bladder cancer cells to anthracycline drugs via inhibiting P-gp expression. Bladder cancer cells that survived transient exposure to anthracycline drugs showed higher levels of P-gp expression and more nuclear localization of Twist than untreated cells. Conclusion: We report a novel mechanism of anthracycline chemoresistance in bladder cancer in which activated Twist mediates P-gp expression in addition to its antiapoptotic roles. Therapeutic strategies targeting Twist may improve the management of recurrent bladder cancer after chemotherapy.