Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration
Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration
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DOI：
10.1038/leu.2008.103
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发表时间：
2008-08-01
期刊：
影响因子：
11.4
通讯作者：
Wulf, G. G.
中科院分区：
文献类型：
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作者：
Chapuy, B.;Koch, R.;Wulf, G. G.
多药耐药（MDR）严重限制了肿瘤和白血病患者化疗的疗效。主动跨膜转运对于这种细胞耐药性是必不可少的，主要由ATP结合盒（ABC）转运蛋白提供。细胞内药物螯合有助于MDR，然而，一个真正的细胞内ABC转运蛋白与MDR功能尚未确定。分析白血病干细胞的内在药物外排能力，我们发现ABC转运蛋白A3（ABCA 3）在急性髓性白血病（AML）样本中一致表达。ABCA 3的更高表达与不利的治疗结果相关，并且在体外，表达升高诱导对广谱细胞生长抑制剂的抗性。ABCA 3仍然位于溶酶体和多泡体的限制膜内，其中细胞抑制剂被有效地隔离。除了AML，我们还在一组淋巴造血组织和转化细胞系中检测到ABCA 3。总之，我们确定了由真正的细胞内ABCA 3介导的亚细胞药物隔离作为内在MDR的临床相关机制。
Multidrug resistance (MDR) seriously limits the efficacy of chemotherapy in patients with cancer and leukemia. Active transport across membranes is essential for such cellular drug resistance, largely provided by ATP-binding cassette (ABC) transport proteins. Intracellular drug sequestration contributes to MDR; however, a genuine intracellular ABC transport protein with MDR function has not yet been identified. Analyzing the intrinsic drug efflux capacity of leukemic stem cells, we found the ABC transporter A3 (ABCA3) to be expressed consistently in acute myeloid leukemia (AML) samples. Greater expression of ABCA3 is associated with unfavorable treatment outcome, and in vitro, elevated expression induces resistance toward a broad spectrum of cytostatic agents. ABCA3 remains localized within the limiting membranes of lysosomes and multivesicular bodies, in which cytostatics are efficiently sequestered. In addition to AML, we also detected ABCA3 in a panel of lymphohematopoietic tissues and transformed cell lines. In conclusion, we identified subcellular drug sequestration mediated by the genuinely intracellular ABCA3 as being a clinically relevant mechanism of intrinsic MDR.