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• W2111661024 abstract "Abstract Glioma-initiating cells (GIC), which are characterized by their self-renewal capacity and tumorigenicity, were recently identified as a highly tumorigenic subpopulation of glioblastoma multiforme and are considered responsible for glioblastoma recurrence and chemo/radiation resistance. Previously, it was revealed that Wnt signaling activation is critical to the self-renewal of GICs. However, the molecular mechanism underlying the high expression of β-catenin, the key transcription factor of the Wnt signaling pathway, remains elusive. In this investigation, it was determined that aurora kinase A (AURKA) regulates the self-renewal and tumorigenicity of GICs by stabilizing β-catenin. In GICs, AURKA directly interacts with AXIN and disrupts the AXIN/GSK3β/β-catenin destruction complex and stabilizes β-catenin, thereby activating Wnt signaling to promote self-renewal. Stable knockdown of AURKA destabilizes β-catenin by increasing phosphorylated β-catenin bound to AXIN and suppresses Wnt signaling, which inhibits the ability of GICs to self-renew. This effect is rescued by expression of an AURKA kinase dead mutant, D274A, which lacks the ability to phosphorylate GSK3β, indicating that stabilization of β-catenin by AURKA in GICs is independent from phosphorylation of GSK3β. Functional experiments confirm that inhibition of AUKRA in GICs could suppress their “stemness,” self-renewal ability, and tumorigenicity both in vitro and in vivo, and these effects could be rescued by stabilized β-catenin mutant. These findings indicate that AURKA competes away the binding of AXIN from β-catenin, induces β-catenin stabilization, and activates Wnt signaling in GICs. Implications: AURKA kinase inhibition could effectively attenuate Wnt signaling, thereby inhibiting the self-renewal and tumorigenicity of GICs, and may be a novel target for glioblastoma treatment strategies. Mol Cancer Res; 11(9); 1101–11. ©2013 AACR." @default.
• W2111661024 created "2016-06-24" @default.
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• W2111661024 date "2013-09-01" @default.
• W2111661024 modified "2023-10-16" @default.
• W2111661024 title "AURKA Governs Self-Renewal Capacity in Glioma-Initiating Cells via Stabilization/Activation of β-catenin/Wnt Signaling" @default.
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• W2111661024 doi "https://doi.org/10.1158/1541-7786.mcr-13-0044" @default.
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