Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-κB, and glucose regulation

Svetlana Kotliarova, Sandra Pastorino, Lara C. Kovell, Yuri Kotliarov, Hua Song, Wei Zhang, Rolanda Bailey, Dragan Maric, Jean Claude Zenklusen, Jeongwu Lee, Howard A. Fine

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

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 has yet to be elucidated. We identified GSK3 as a regulator of glioblastoma multiforme cell survival using microarray analysis and small-molecule and genetic inhibitors of GSK3 activity. Various molecular and genetic approaches were then used to dissect out the molecular mechanisms responsible for GSK3 inhibition-induced cytotoxicity. We show 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 tumor necrosis factor-related apoptosis-inducing ligand expression and subsequent cytotoxicity. Additionally, down-regulation of GSK3 activity results in alteration of intracellular glucose metabolism resulting in dissociation of hexokinase II from the outer mitochondrial membrane with subsequent mitochondrial destabilization. Finally, inhibition of GSK3 activity causes a dramatic decrease in intracellular nuclear factor-kappa;B 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.

Original languageEnglish (US)
Pages (from-to)6643-6651
Number of pages9
JournalCancer Research
Volume68
Issue number16
DOIs
StatePublished - Aug 15 2008

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Glycogen Synthase Kinase 3
Glioma
Cell Death
Glucose
Glioblastoma
Cell Survival
Down-Regulation
Phosphorylation
Apoptosis
Hexokinase
Protein-Serine-Threonine Kinases
Cytotoxins
Mitochondrial Membranes
Enzymes
Microarray Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-κB, and glucose regulation. / Kotliarova, Svetlana; Pastorino, Sandra; Kovell, Lara C.; Kotliarov, Yuri; Song, Hua; Zhang, Wei; Bailey, Rolanda; Maric, Dragan; Zenklusen, Jean Claude; Lee, Jeongwu; Fine, Howard A.

In: Cancer Research, Vol. 68, No. 16, 15.08.2008, p. 6643-6651.

Research output: Contribution to journalArticle

Kotliarova, S, Pastorino, S, Kovell, LC, Kotliarov, Y, Song, H, Zhang, W, Bailey, R, Maric, D, Zenklusen, JC, Lee, J & Fine, HA 2008, 'Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-κB, and glucose regulation', Cancer Research, vol. 68, no. 16, pp. 6643-6651. https://doi.org/10.1158/0008-5472.CAN-08-0850
Kotliarova, Svetlana ; Pastorino, Sandra ; Kovell, Lara C. ; Kotliarov, Yuri ; Song, Hua ; Zhang, Wei ; Bailey, Rolanda ; Maric, Dragan ; Zenklusen, Jean Claude ; Lee, Jeongwu ; Fine, Howard A. / Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-κB, and glucose regulation. In: Cancer Research. 2008 ; Vol. 68, No. 16. pp. 6643-6651.
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AU - Song, Hua

AU - Zhang, Wei

AU - Bailey, Rolanda

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AU - Fine, Howard A.

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