Drug Resistance Mechanism and Modulation Group, Ligue 2013 Certified, Bases Moléculaires et Structurales des Systèmes Infectieux, UMR5086, Centre National de la Recherche Scientifique, Université de Lyon, Institut de Biologie et Chimie des Protéines, University of Lyon Lyon, France.
Front Pharmacol. 2013 Nov 7;4:138. doi: 10.3389/fphar.2013.00138. eCollection 2013.
ABCG2 is a key human ATP-binding cassette (ABC) transporter mediating cancer cell chemoresistance. In the case of ABCC1, another multidrug transporter, earlier findings documented that certain modulators greatly increase ABCC1-mediated glutathione (GSH) efflux and, upon depletion of intracellular GSH, induce "collateral sensitivity" leading to the apoptosis of multidrug resistant cells. Recently, it has been suggested that ABCG2 may mediate an active GSH transport. In order to explore if ABCG2-overexpressing cells may be similarly targeted, we first looked for the effects of ABCG2 expression on cellular GSH levels, and for an ABCG2-dependent GSH transport in HEK293 and MCF7 cells. We found that, while ABCG2 overexpression altered intracellular GSH levels in these transfected or drug-selected cells, ABCG2 inhibitors or transport modulators did not influence GSH efflux. We then performed direct measurements of drug-stimulated ATPase activity and (3)H-GSH transport in inside-out membrane vesicles of human ABC transporter-overexpressing Sf9 insect cells. Our results indicate that ABCG2-ATPase is not modulated by GSH and, in contrast to ABCC1, ABCG2 does not catalyze any significant GSH transport. Our data suggest no direct interaction between the ABCG2 transporter and GSH, although a long-term modulation of cellular GSH by ABCG2 cannot be excluded.
ABCG2 是一种关键的人类三磷酸腺苷结合盒（ABC）转运蛋白，介导癌细胞的化疗耐药性。对于另一种多药转运蛋白 ABCC1，早期的研究结果表明，某些调节剂可显著增加 ABCC1 介导的谷胱甘肽（GSH）外排，当细胞内 GSH 耗尽时，会诱导“代偿性敏感性”，导致多药耐药细胞凋亡。最近，有人提出 ABCG2 可能介导活性 GSH 转运。为了探讨 ABCG2 过表达的细胞是否也可以被靶向，我们首先研究了 ABCG2 表达对细胞内 GSH 水平的影响，以及在 HEK293 和 MCF7 细胞中是否存在 ABCG2 依赖性的 GSH 转运。我们发现，虽然 ABCG2 过表达改变了这些转染或药物选择的细胞内 GSH 水平，但 ABCG2 抑制剂或转运调节剂并不影响 GSH 外排。然后，我们在人 ABC 转运蛋白过表达的 Sf9 昆虫细胞的外翻膜囊泡中进行了药物刺激的 ATP 酶活性和（3）H-GSH 转运的直接测量。我们的结果表明，GSH 不调节 ABCG2-ATP 酶，并且与 ABCC1 相反，ABCG2 不催化任何显著的 GSH 转运。我们的数据表明，ABCG2 转运体与 GSH 之间没有直接相互作用，尽管不能排除 ABCG2 对细胞内 GSH 的长期调节作用。
