Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation.
Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation.
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DOI：
10.1158/0008-5472.can-08-0850
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发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Fine HA
中科院分区：
文献类型：
--
作者：
Kotliarova S;Pastorino S;Kovell LC;Kotliarov Y;Song H;Zhang W;Bailey R;Maric D;Zenklusen JC;Lee J;Fine HA
Glycogen synthase kinase-3 (GSK3), a serine/threonine kinase, is involved in diverse cellular processes ranging from nutrient and energy homeostasis to proliferation and apoptosis. Its role in glioblastoma multiforme (GBM) has yet to be elucidated. We identified GSK3 as a regulator of GBM cell survival using microarray analysis, small molecule and genetic inhibitors of GSK3 activity. Various molecular and genetic approaches were then employed to dissect out the molecular mechanisms responsible for GSK3 inhibition-induced cytotoxicity. We demonstrate that multiple small molecular inhibitors of GSK3 activity and genetic down-regulation of GSK3α/β significantly inhibit glioma cell survival and clonogenicity. The potency of the cytotoxic effects is directly correlated with decreased enzyme activity-activating phosphorylation of GSK3α/β Y276/Y216 and with increased enzyme activity-inhibitory phosphorylation of GSK3α S21. Inhibition of GSK3 activity results in c-MYC activation leading to the induction of Bax, Bim, DR4/DR5 and TRAIL expression and subsequent cytotoxicity. Additionally, down-regulation of GSK3 activity results in alteration of intracellular glucose metabolism resulting in dissociation of hexokinase-II (HKII) from the outer mitochondrial membrane with subsequent mitochondrial destabilization. Finally, inhibition of GSK3 activity causes a dramatic decrease in intracellular nuclear factor-kappa B (NF-κB) activity. Inhibition of GSK3 activity results in c-MYC dependent glioma cell death through multiple mechanisms, all of which converge on the apoptotic pathways. GSK3 may therefore be an important therapeutic target for gliomas. Future studies will further define the optimal combinations of GSK3 inhibitors and cytotoxic agents for use in gliomas and other cancers.
