AURKA governs self-renewal capacity in glioma-initiating cells via stabilization/activation of ß-catenin/Wnt signaling.

UNLABELLED: 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 ß-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 ß-catenin. In GICs, AURKA directly interacts with AXIN and disrupts the AXIN/GSK3ß/ß-catenin destruction complex and stabilizes ß-catenin, thereby activating Wnt signaling to promote self-renewal. Stable knockdown of AURKA destabilizes ß-catenin by increasing phosphorylated ß-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 GSK3ß, indicating that stabilization of ß-catenin by AURKA in GICs is independent from phosphorylation of GSK3ß. 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 ß-catenin mutant. These findings indicate that AURKA competes away the binding of AXIN from ß-catenin, induces ß-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.