Activation of glycogen synthase kinase 30 disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity
Activation of glycogen synthase kinase 30 disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity
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DOI：
10.1158/0008-5472.can-05-1925
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Shulga, N
中科院分区：
文献类型：
--
作者：
Pastorino, JG;Hoek, JB;Shulga, N
转化后的细胞高度糖酵解并过度表达己糖激酶II （HXK II）。HXK II能够通过与电压依赖性阴离子通道（VDAC）相互作用与线粒体结合，VDAC是一种丰富的线粒体外膜蛋白。HYK II与线粒体的结合已被证明可以防止细胞活力的丧失。Akt激活部分通过促进HXK II与线粒体结合抑制细胞凋亡，但Akt实现这一作用的机制尚未明确。本报告表明，Akt通过负调控糖原合成酶激酶3 β (GSK3 β)的活性介导HXK II与线粒体的结合。在AU的抑制下，GSK3 β被激活并磷酸化VDAC。WXK II不能结合被GSK3 β磷酸化的VDAC并与线粒体分离。Akt的抑制增强了化疗诱导的细胞毒性，这种作用依赖于GSK3 β的激活及其伴随的破坏HXK II与线粒体结合的能力。此外，在没有Akt抑制或GSK3 β活化的情况下，可以迫使HXK II从线粒体分离的药物与化疗药物联合使用时，可以促进细胞杀伤的协同增加。这些发现表明，干扰HXK II与线粒体的结合可能是一种可行的方式，可以增强传统化疗药物的疗效。
Transformed cells are highly glycolytic and overexpress hexokinase II (HXK II). HXK II is capable of binding to the mitochondria through an interaction with the voltage-dependent anion channel (VDAC), an abundant outer mitochondrial membrane protein. The binding of HYK II to mitochondria has been shown to protect against loss of cell viability. Akt activation inhibits apoptosis partly by promoting the binding of HXK II to the mitochondria, but the mechanism through which Akt accomplishes this has not been characterized. The present report shows that Akt mediates the binding of HXK II to the mitochondria by negatively regulating the activity of glycogen synthase kinase 3 beta (GSK3 beta). On inhibition of AU, GSK3 beta is activated and phosphorylates VDAC. WXK II is unable to bind VDAC phosphorylated by GSK3 beta and dissociates from the mitochondria. Inhibition of Akt potentiates chemotherapy-induced cytotoxicity, an effect that is dependent on GSK3 beta activation and its attendant ability to disrupt the binding of HXK II to the mitochondria. Moreover, agents that can force the detachment of HXK II from mitochondria in the absence of Akt inhibition or GSK3 beta activation promoted a synergistic increase in cell killing when used in conjunction with chemotherapeutic drugs. Such findings indicate that interference with the binding of HXK II to mitochondria may be a practicable modality by which to potentiate the efficacy of conventional chemotherapeutic agents.