Glutathione influences c-Myc-induced apoptosis in M14 human melanoma cells
Glutathione influences c-Myc-induced apoptosis in M14 human melanoma cells
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DOI：
10.1074/jbc.m207684200
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发表时间：
2002-11-15
影响因子：
4.8
通讯作者：
Ciriolo, MR
中科院分区：
文献类型：
--
作者：
Biroccio, A;Benassi, B;Ciriolo, MR
本文的目的是剖析c-Myc下调诱导黑色素瘤细胞程序性死亡的机制。在稳定和多西环素诱导的M14黑色素瘤细胞，下调c-Myc诱导细胞凋亡后，细胞内还原型谷胱甘肽含量减少，并伴随其氧化形式的积累。这种氧化还原改变与γ-谷氨酰-半胱氨酸合成酶和NADPH依赖性GSSG还原酶的酶活性降低，以及随之而来的谷胱甘肽在细胞外介质中的释放有关。细胞色素c在细胞凋亡诱导的早期阶段释放到细胞溶质中，早在可检测到活性氧的产生和半胱天冬酶-9和-3的活化之前。宏阵列分析显示，下调c-Myc产生显著变化的基因表达的部分相关的代谢，γ-谷氨酰-半胱氨酸合成酶和GSSG还原酶的表达被发现显着减少。加入N-乙酰-L-半胱氨酸或谷胱甘肽乙酯可抑制凋亡过程，从而证实谷胱甘肽在c-Myc诱导的程序性细胞死亡中的关键作用。
The objective of this article is to dissect the mechanisms by which the down-regulation of c-Myc induces programmed cell death in melanoma cells. In stable and doxycycline-inducible M14 melanoma cells, down-regulation of c-Myc induced apoptosis subsequent to a decrease in the intracellular reduced glutathione content and a concomitant accumulation of its oxidized form. This redox alteration was associated with a decrease of the enzyme activities of gamma-glutamyl-cysteine synthetase and NADPH-dependent GSSG reductase, as well as a consequent glutathione release in the extracellular medium. Cytochrome c was released into the cytosol at very early stages of apoptosis induction, long before detectable production of reactive oxygen species and activation of caspase-9 and -3. Macroarray analysis revealed that down-regulation of c-Myc produced striking changes in gene expression in the section related to metabolism, where the expression of gamma-glutamyl-cysteine synthetase and GSSG reductase was found to be significantly reduced. The addition of N-acetyl-L-cysteine or glutathione ethyl ester inhibited the apoptotic process, thus confirming the key role of glutathione in programmed cell death induced by c-Myc.