Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Independencia, Santiago 8380453, Chile.
Asian J Androl. 2019 Sep-Oct;21(5):460-467. doi: 10.4103/aja.aja_1_19.
One of the factors promoting tumoral progress is the abnormal activation of the epithelial-mesenchymal transition (EMT) program which has been associated with chemoresistance in tumoral cells. The transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), a key EMT activator, has recently been related to docetaxel resistance, the main chemotherapeutic used in advanced prostate cancer treatment. The mechanisms involved in this protective effect are still unclear. In a previous work, we demonstrated that ZEB1 expression induced an EMT-like phenotype in prostate cancer cell lines. In this work, we used prostate cancer cell lines 22Rv1 and DU145 to study the effect of ZEB1 modulation on docetaxel resistance and its possible mechanisms. The results showed that ZEB1 overexpression conferred to 22Rv1 cell resistance to docetaxel while its silencing made DU145 cells more sensitive to it. Analysis of resistance markers showed no presence of ATP-binding cassette subfamily B member 1 (MDR1) and no changes in breast cancer resistance protein (BCRP) or ATP-binding cassette subfamily C member 10 (MRP7). However, a correlation between ZEB1, multidrug resistance-associated protein 1 (MRP1), and ATP-binding cassette subfamily C member 4 (MRP4) expression was observed. MRP4 inhibition, using MK571, resensitized cells with ZEB1 overexpression to docetaxel treatment. In addition, modulation of ZEB1 and subsequent change in MRP4 expression correlated with a lower apoptotic response to docetaxel, characterized by lower B-cell lymphoma 2 (Bcl2), high BCL2-associated X protein (Bax), and high active caspase 3 expression. The response to docetaxel in our model seems to be mediated mainly by activation of the apoptotic death program. Our results showed that modulation of MRP4 could be a mediator of ZEB1-related resistance to docetaxel in prostate cancer, making it a possible marker for chemotherapy response in patients who do not express MDR1.
促进肿瘤进展的因素之一是上皮-间充质转化（EMT）程序的异常激活，该程序与肿瘤细胞的化疗耐药性有关。锌指 E 盒结合同源盒 1（ZEB1）转录因子是 EMT 的关键激活因子，最近与多西他赛耐药有关，多西他赛是治疗晚期前列腺癌的主要化疗药物。这种保护作用的机制尚不清楚。在之前的工作中，我们证明了 ZEB1 表达在前列腺癌细胞系中诱导 EMT 样表型。在这项工作中，我们使用前列腺癌细胞系 22Rv1 和 DU145 来研究 ZEB1 调节对多西他赛耐药性的影响及其可能的机制。结果表明，ZEB1 过表达使 22Rv1 细胞对多西他赛产生耐药性，而沉默使其对多西他赛更敏感。耐药标志物分析显示不存在 ABC 转运蛋白 B 亚家族成员 1（MDR1），乳腺癌耐药蛋白（BCRP）或 ABC 转运蛋白 C 亚家族成员 10（MRP7）没有变化。然而，观察到 ZEB1、多药耐药相关蛋白 1（MRP1）和 ABC 转运蛋白 C 亚家族成员 4（MRP4）表达之间存在相关性。使用 MK571 抑制 MRP4 使 ZEB1 过表达的细胞对多西他赛治疗重新敏感。此外，ZEB1 的调节及其随后的 MRP4 表达变化与对多西他赛的较低凋亡反应相关，其特征是 B 细胞淋巴瘤 2（Bcl2）降低，BCL2 相关 X 蛋白（Bax）高和活性 caspase 3 高表达。我们模型中的多西他赛反应似乎主要通过激活凋亡死亡程序来介导。我们的结果表明，MRP4 的调节可能是 ZEB1 相关多西他赛耐药性在前列腺癌中的介质，使其成为不表达 MDR1 的患者化疗反应的可能标志物。
