Overexpression of Mcl-1 Confers Multidrug Resistance, Whereas Topoisomerase IIβ Downregulation Introduces Mitoxantrone-Specific Drug Resistance in Acute Myeloid Leukemia
Overexpression of Mcl-1 Confers Multidrug Resistance, Whereas Topoisomerase IIβ Downregulation Introduces Mitoxantrone-Specific Drug Resistance in Acute Myeloid Leukemia
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DOI：
10.1124/mol.113.086140
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发表时间：
2013-08-01
影响因子：
3.6
通讯作者：
Xing, Chengguo
中科院分区：
文献类型：
--
作者：
Hermanson, David L.;Das, Sonia G.;Xing, Chengguo
耐药性是癌症治疗中的一个严重挑战，可以通过多种机制获得。这些分子变化可能会对不同的治疗产生不同程度的耐药性，需要进行表征以选择最佳治疗。最近发现的小分子，乙基-2-氨基-6-（3，5-二甲氧基苯基）-4-（2-乙氧基-2-氧代乙基）-4H-色烯3-羧酸酯（CXL 017），揭示了对耐药白血病的选择性细胞毒性。耐药急性髓性白血病细胞系HL 60/MX2在慢性暴露后也未能获得对CXL 017的抗性，并重新获得对标准疗法的敏感性。本研究旨在探讨HL 60/MX 2细胞耐药的机制及其再敏感的分子基础。结果显示，相对于亲本细胞系HL 60及其再致敏细胞系HL 60/MX2/CXL 017，HL 60/MX2细胞系具有升高的Mcl-1蛋白水平，而其具有降低的拓扑异构酶II β水平。HL 60/MX2细胞中Mcl-1的过表达主要通过磷酸化细胞外信号调节蛋白激酶1和2介导的Mcl-1稳定化来调节，而HL 60/MX2细胞中拓扑异构酶IIb的减少则通过遗传下调来控制。上调Mcl-1会对标准疗法产生多药耐药性，而下调Mcl-1会导致显著的细胞死亡。下调拓扑异构酶IIb赋予特异性对米托蒽醌的抗性，而不是对其他拓扑异构酶II抑制剂的抗性。总体而言，这些数据表明，Mcl-1过表达是标准治疗交叉耐药的关键决定因素，而拓扑异构酶IIb下调是特异性的米托蒽醌耐药。
Drug resistance is a serious challenge in cancer treatment and can be acquired through multiple mechanisms. These molecular changes may introduce varied extents of resistance to different therapies and need to be characterized for optimal therapy choice. A recently discovered small molecule, ethyl-2-amino-6-( 3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene3- carboxylate) (CXL017), reveals selective cytotoxicity toward drug-resistant leukemia. A drug-resistant acute myeloid leukemia cell line, HL60/MX2, also failed to acquire resistance to CXL017 upon chronic exposure and regained sensitivity toward standard therapies. In this study, we investigated the mechanisms responsible for HL60/MX2 cells' drug resistance and the molecular basis for its resensitization. Results show that the HL60/MX2 cell line has an elevated level of Mcl-1 protein relative to the parental cell line, HL60, and its resensitized cell line, HL60/MX2/CXL017, whereas it has a reduced level of topoisomerase II beta. Mcl-1 overexpression in HL60/MX2 cells is mainly regulated through phospho-extracellular signal-regulated protein kinases 1 and 2-mediated Mcl-1 stabilization, whereas the reduction of topoisomerase IIb in HL60/MX2 cells is controlled through genetic downregulation. Upregulating Mcl-1 introduces multidrug resistance to standard therapies, whereas its downregulation results in significant cell death. Downregulating topoisomerase IIb confers resistance specifically to mitoxantrone, not to other topoisomerase II inhibitors. Overall, these data suggest that Mcl-1 overexpression is a critical determinant for cross-resistance to standard therapies, whereas topoisomerase IIb downregulation is specific to mitoxantrone resistance.