Department of Urology, The First Hospital of Xi'an Jiaotong University, Xi'an, PR China.
Chemotherapy. 2012;58(4):264-72. doi: 10.1159/000341860. Epub 2012 Sep 12.
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.
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.
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.
膜转运蛋白 P-糖蛋白（P-gp）被发现介导化疗耐药性，这是几种人类癌症中有效化疗的障碍之一。转录因子 Twist 已被报道参与癌症侵袭和转移，在化疗耐药性的进展中也起着至关重要的作用。然而，Twist 对 P-gp 相关化疗耐药性的影响仍存在争议。
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，在人膀胱癌细胞和组织中发现 Twist 与 P-gp 共表达，与增强对蒽环类药物的化疗耐药性有关。其次，通过特异性 siRNA 处理敲低 Twist 可通过抑制 P-gp 表达显著增加膀胱癌细胞对蒽环类药物的敏感性。短暂暴露于蒽环类药物的膀胱癌细胞比未处理的细胞表现出更高水平的 P-gp 表达和更多的核定位 Twist。
我们报告了膀胱癌中蒽环类化疗耐药性的一种新机制，其中激活的 Twist 除了发挥抗细胞凋亡作用外，还介导 P-gp 的表达。针对 Twist 的治疗策略可能会改善化疗后复发性膀胱癌的管理。
