title: AURKA governs self-renewal capacity in glioma-initiating cells via stabilization/activation of β-catenin/Wnt signaling.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurosurgery, The 1st Affiliated Hospital of Sun Yat-Sen University, No 58, Zhongshan 2 Road, Guangzhou, Guangdong Province 510080, China. zhangxiaonu@gmail.com.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Xia
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Ding
authors.forename: Lixuan
authors.initials: L
authors.lastname: Yang
authors.forename: Zhengsong
authors.initials: Z
authors.lastname: Huang
authors.forename: Nu
authors.initials: N
authors.lastname: Zhang
mesh_terms: D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D060466:Axin Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010766:Phosphorylation; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060466:Axin Protein; D051153:Wnt Proteins; D051176:beta Catenin; C576917:AURKA protein, human; D064096:Aurora Kinase A