1. Academic Validation
  2. Targeting Aurora kinase B attenuates chemoresistance in glioblastoma via a synergistic manner with temozolomide

Targeting Aurora kinase B attenuates chemoresistance in glioblastoma via a synergistic manner with temozolomide

  • Pathol Res Pract. 2019 Nov;215(11):152617. doi: 10.1016/j.prp.2019.152617.
Wahafu Alafate 1 Maode Wang 2 Jie Zuo 3 Wei Wu 1 Liangzhang Sun 3 Chao Liu 4 Wanfu Xie 1 Jia Wang 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
  • 2 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China; Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
  • 3 The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, PR China.
  • 4 Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China; Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. Electronic address: jiawang_xjtu@163.com.
Abstract

Background: Recent studies have demonstrated that aberrant expression or activation of kinases results in oncogenesis of a wide range of cancers including GBM. Inhibition of kinases expression induces a reduction of therapy resistance. In this study, we investigate the underlying mechanism by which glioblastoma (GBM) cells acquire resistance to Temozolomide (TMZ) through Aurora Kinase B (AURKB) thus to identify novel therapeutic targets and prognostic biomarkers for GBM.

Methods: AURKB was identified as a key candidate kinase-encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of AURKB in oncogenesis and chemoresistance were investigated by lentivirus-dependent silencing of AURKB combined with qRT-PCR, western blot and in vivo intra-cranial xenograft mice models. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. Lastly, Chou-Talalay method was used to confirm the synergistic effect of TMZ combined with AURKB inhibitor.

Results: AURKB was among the most significantly up-regulated kinase-coding genes in TMZ resistant GBM cells according to database GSE68029, moreover, an increased expression of AURKB was closely associated with poor prognosis in glioma and GBM patients. AURKB knock-down resensitized U87 resistant cells to TMZ both in vitro and in vivo. Additionally, the combination of TMZ and Hesperadin, a specific AURKB inhibitor, significantly suppressed the proliferation of TMZ resistant GBM cells thus dramatically prolonged the survival of xenograft mice viaa synergistic effect with TMZ.

Conclusion: Elevated AURKB expression was strongly correlated to TMZ resistant acquisition and poor prognosis, furthermore, targeting AURKB would be a potential therapeutic target for GBM patients.

Keywords

AURKB; GBM; Hesperadin; Temozolomide; Therapy resistance.

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