Glutathione depletion regulates both extrinsic and intrinsic apoptotic signaling cascades independent from multidrug resistance protein 1.
Glutathione depletion regulates both extrinsic and intrinsic apoptotic signaling cascades independent from multidrug resistance protein 1.
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DOI：
10.1007/s10495-013-0900-0
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发表时间：
2014-01
期刊：
影响因子：
7.2
通讯作者：
Cidlowski, John A.
中科院分区：
文献类型：
--
作者：
Franco, Rodrigo;Bortner, Carl D.;Schmitz, Ingo;Cidlowski, John A.
谷胱甘肽（GSH）耗竭是细胞凋亡的重要标志。我们以前证明，谷胱甘肽耗竭，通过其流出，调节凋亡的调节刽子手半胱天冬酶活性。然而，涉及的GSH转运蛋白的分子身份和调节GSH损失的信号级联仍然不清楚。我们试图确定多药耐药蛋白1（MRP1）在GSH耗竭中的作用及其对细胞凋亡的外在和内在途径的调节作用。在人淋巴瘤细胞中，GSH耗竭被刺激，而不是通过MK571药理学阻断MRP 1抑制。GSH损失依赖于起始半胱天冬酶8和9的活性。通过短发夹小干扰RNA稳定转染的MRP1基因敲低（>60%）显著降低了MRP1蛋白水平，这与MRP1介导的阴离子转运的丧失直接相关。然而，GSH耗竭和细胞凋亡诱导的外在和内在的途径不受MRP1敲低。有趣的是，通过MK571刺激GSH损失也通过刺激引发剂半胱天冬酶8和9活性以及促凋亡BID裂解来增强凋亡的引发阶段。我们的研究结果清楚地表明，半胱天冬酶依赖的GSH损失和细胞凋亡不介导的MRP 1蛋白和GSH耗竭刺激淋巴细胞凋亡的起始阶段。
Glutathione (GSH) depletion is an important hallmark of apoptosis. We previously demonstrated that GSH depletion, by its efflux, regulates apoptosis by modulation of executioner caspase activity. However, both the molecular identity of the GSH transporter(s) involved and the signaling cascades regulating GSH loss remain obscure. We sought to determine the role of multidrug resistance protein 1 (MRP1) in GSH depletion and its regulatory role on extrinsic and intrinsic pathways of apoptosis. In human lymphoma cells, GSH depletion was stimulated rather than inhibited by pharmacological blockage of MRP1 with MK571. GSH loss was dependent on initiator caspases 8 and 9 activity. Genetic knock-down (>60%) of MRP1 by stable transfection with short-hairpin small interfering RNA significantly reduced MRP1 protein levels, which correlated directly with the loss of MRP1-mediated anion transport. However, GSH depletion and apoptosis induced by both extrinsic and intrinsic pathways were not affected by MRP1 knock-down. Interestingly, stimulation of GSH loss by MK571 also enhanced the initiator phase of apoptosis by stimulating initiator caspase 8 and 9 activity and pro-apoptotic BID cleavage. Our results clearly show that caspase-dependent GSH loss and apoptosis are not mediated by MRP1 proteins and that GSH depletion stimulates the initiation phase of apoptosis in lymphoid cells.
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