Expression of multidrug resistance protein-3 (multispecific organic anion transporter-D) in human embryonic kidney 293 cells confers resistance to anticancer agents.
Expression of multidrug resistance protein-3 (multispecific organic anion transporter-D) in human embryonic kidney 293 cells confers resistance to anticancer agents.
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发表时间：
1999-12
期刊：
影响因子：
11.2
通讯作者：
H. Zeng;Lisa J. Bain;M. Belinsky;G. Kruh
中科院分区：
文献类型：
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作者：
H. Zeng;Lisa J. Bain;M. Belinsky;G. Kruh
多药耐药相关蛋白（MRP）1和小管多特异性有机阴离子转运蛋白（cMOAT）/MRP 2是ATP结合盒（ABC）转运蛋白，赋予对天然产物细胞毒性药物的抗性。我们最近描述了四个人MRP/cMOAT亚家族成员的完整编码序列，并发现在这些蛋白质中，MRP 3/MOAT-D与MRP 1最密切相关（58%同一性; M. G. Belinsky和G. D.克鲁湾J. Cancer，80：1342-1349，1999）。在本研究中，我们试图确定MRP 3是否能够赋予对细胞毒性药物的抗性。为了解决这一问题，用MRP 3表达载体转染人胚肾293细胞，并分析转染细胞的耐药性表型。与对照转染细胞相比，MRP 3转染细胞对依托泊苷的耐药性约为4倍，对长春新碱的耐药性约为2倍。此外，观察到抗代谢药甲氨蝶呤的耐药性约为1.7倍。对其他几种天然产物药物，包括蒽环类和紫杉醇，未观察到耐药性增加。MRP转染的细胞表现出放射性标记的依托泊苷的蓄积减少，与质膜外排泵的操作一致。这些结果表明，MRP 3赋予一些抗癌药物的耐药性，但其耐药模式是不同的其他ABC转运蛋白参与耐药性天然产物化疗药物的耐药模式。
Multidrug resistance-associated protein (MRP)1 and canalicular multispecific organic anion transporter (cMOAT)/MRP2 are ATP-binding cassette (ABC) transporters that confer resistance to natural product cytotoxic drugs. We recently described the complete coding sequences of four human MRP/cMOAT subfamily members and found that, among these proteins, MRP3/MOAT-D is most closely related to MRP1 (58% identity; M. G. Belinsky and G. D. Kruh, Br. J. Cancer, 80: 1342-1349, 1999). In the present study, we sought to determine whether MRP3 is capable of conferring resistance to cytotoxic drugs. To address this question, human embryonic kidney 293 cells were transfected with an MRP3 expression vector, and the drug resistance phenotype of the transfected cells was analyzed. The MRP3-transfected cells displayed approximately 4-fold resistance to etoposide and approximately 2-fold resistance to vincristine, compared with control transfected cells. In addition, approximately 1.7-fold resistance was observed for the antimetabolite methotrexate. Increased resistance was not observed for several other natural product agents, including anthracyclines and Taxol. The MRP-transfected cells exhibited reduced accumulation of radiolabeled etoposide, consistent with the operation of a plasma membrane efflux pump. These results indicate that MRP3 confers resistance to some anticancer agents but that its resistance pattern is distinct from the resistance patterns of other ABC transporters involved in resistance to natural product chemotherapeutic agents.