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- W4361943324 abstract "<div>Abstract<p><b>Purpose:</b> Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3β (GSK3β), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma.</p><p><b>Experimental Design:</b> The active fraction of GSK3β that is phosphorylated at the tyrosine 216 residue (pGSK3β<sup>Y216</sup>) was identified in glioblastoma cell lines. GSK3β activity for phosphorylating its substrate was detected in these cells by nonradioisotopic <i>in vitro</i> kinase assay.</p><p><b>Results:</b> Higher expression levels of GSK3β and pGSK3β<sup>Y216</sup> were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3β activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells <i>in vitro</i>. Inhibition of GSK3β was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type <i>p53</i> and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation.</p><p><b>Conclusion:</b> These results indicate that GSK3β exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways. Consequently, we propose that GSK3β provides a potential therapeutic target in glioblastoma.</p></div>" @default.
- W4361943324 created "2023-04-05" @default.
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- W4361943324 date "2023-03-31" @default.
- W4361943324 modified "2023-10-14" @default.
- W4361943324 title "Data from Potential Therapeutic Effect of Glycogen Synthase Kinase 3β Inhibition against Human Glioblastoma" @default.
- W4361943324 doi "https://doi.org/10.1158/1078-0432.c.6517524" @default.
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