Regulation of glycogen synthase kinase-3 beta (GSK-3β) by the Ala pathway in gliomas

Gliomas are aggressive brain tumours that, despite advances in multimodal therapies, continue to portend a dismal prognosis. Glioblastoma multiforme (GBM) represents the most aggressive glioma and patients have a median survival of 14 months, even with the best available treatments. The phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3 beta (GSK-3 beta) and Wnt/beta-catenin pathways are dysregulated in a number of cancers, and these two pathways share a common node protein, GSK-3 beta. This protein is responsible for the regulation/degradation of beta-catenin, which reduces beta-catenin's translocation to the nucleus and influences the subsequent transcription of oncogenes. The non-specific small-molecule GSK-3 beta inhibitor, lithium chloride (LiCl), and the specific Akt inhibitor, AktX, were used to treat U87MG and U87MG.Delta 2-7 human glioma cell lines. LiCl treatment significantly affected cell morphology of U87MG and U87MG.Delta 2-7 cells, while also increasing levels of phospho-GSK-3 beta in a dose-dependent manner. Increased cell proliferation was observed at low-to-mid LiCl concentrations as determined by MTT cell growth assays. Treatment of U87MG and U87MG.Delta 2-7 cells with AktX resulted in reduced levels of phospho-GSK-3 beta through its inhibition of Akt, in addition to decreased levels of phosphorylated (active) Akt in a dose-dependent fashion. We have shown in this study that GSK-3 beta regulation by phosphorylation is important for cell morphology and growth, and that LiCl enhances growth of U87MG and U87MG.Delta 2-7 cells by inhibiting GSK-3 beta through its phosphorylation, whereas AktX reduces growth via activation of GSK-3 beta by inhibiting Akt's,kinase activity. (C) 2012 Published by Elsevier Ltd.