Lithium chloride decreases proliferation and migration of C6 glioma cells harboring isocitrate dehydrogenase 2 mutant via GSK-3β

Abstract

The gene encoding isocitrate dehydrogenase (IDH) is somatically mutated predominantly in secondary glioblastoma multiforme. Mutations of IDH1 and IDH2 lead to simultaneous loss and gain of activities in the production of α-ketoglutarate and 2-hydroxyglutarate, respectively. Lithium chloride was recently proved efficient in inhibiting glioma cell migration. The mechanism of lithium chloride on C6 glioma cells harboring IDH2 mutation has not been studied. Here, we found lithium chloride induced inhibitive effects on cell proliferation of both C6 glioma cells with and without IDH2 mutation, although IDH2 mutation increased the stability of HIF-1α. GSK-3β could be phosphorylated at Ser9 and its activity was inhibited when C6 glioma cells were treated by lithium chloride. The degree of phosphorylation in IDH2(R172G) treatment group was lower than that as compared to the control and IDH2 treatment groups. At the same time, the accumulation of β-catenin in C6 cell nucleus was decreased. Moreover, although the β-catenin and HIF-1α increased the secretion of metalloproteinase-2,-9 in C6 glioma cells harboring IDH2 mutation, the migration potential of lithium chloride-treated C6 glioma cells harboring the IDH2 and its mutant was uniform. These results indicated lithium chloride could decrease the proliferation and migration potential of C6 glioma cells harboring IDH2 mutation.

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

“…Gliomas are the most common type of human brain tumors and contain specific histologic subtypes with most common forms as astrocytomas, oligodendrogliomas and ependymomas (Fu et al 2014). These tumors are classified as grades I-IV on the basis of histopathological and clinical criteria established by the World Health Organization (WHO) (Fu et al 2014).…”

“…These tumors are classified as grades I-IV on the basis of histopathological and clinical criteria established by the World Health Organization (WHO) (Fu et al 2014). Generally, WHO grade I gliomas are mostly curable with total surgical resection and rarely evolve into higher-grade lesions (Fu et al 2014). In contrast, gliomas of WHO grade II or III are invasive, progress to higher-grade lesions and have a poorer outcome (Fu et al 2014).…”

“…Generally, WHO grade I gliomas are mostly curable with total surgical resection and rarely evolve into higher-grade lesions (Fu et al 2014). In contrast, gliomas of WHO grade II or III are invasive, progress to higher-grade lesions and have a poorer outcome (Fu et al 2014). The grade IV glioma known as glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults and can develop either from de novo (primary GBM) or through progression from low-grade tumors (secondary GBM) (Fu et al 2014).…”

“…In contrast, gliomas of WHO grade II or III are invasive, progress to higher-grade lesions and have a poorer outcome (Fu et al 2014). The grade IV glioma known as glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults and can develop either from de novo (primary GBM) or through progression from low-grade tumors (secondary GBM) (Fu et al 2014). GBM remains one of the most devastating diseases known to man and affects more than 17,000 patients in the USA alone every year (Soritau et al 2011).…”

“…The gene encoding isocitrate dehydrogenase-1 (IDH1) is mutated mainly in secondary GBM (Fu et al 2014). However, the frequencies of mutations in isocitrate dehydrogenase-2 (IDH2) in these gliomas are rare (Fu et al 2014).…”