Molecular and Cellular Biochemistry

, Volume 370, Issue 1, pp 89–102

Long-term exposure to imatinib reduced cancer stem cell ability through induction of cell differentiation via activation of MAPK signaling in glioblastoma cells

  • Yucui Dong
  • Qinglian Han
  • Yan Zou
  • Zhenling Deng
  • Xinliang Lu
  • Xiaohua Wang
  • Weihua Zhang
  • Hua Jin
  • Jun Su
  • Tao Jiang
  • Huan Ren
Article

DOI: 10.1007/s11010-012-1401-0

Cite this article as:
Dong, Y., Han, Q., Zou, Y. et al. Mol Cell Biochem (2012) 370: 89. doi:10.1007/s11010-012-1401-0

Abstract

Glioblastoma multiforme (GBM) was shown to harbor therapy-resistant cancer stem cells that were major causes of recurrence. PDGFR (platelet-derived growth factor receptor) and c-Kit (stem cell factor receptor) signaling play important roles in initiation and maintenance of malignant glioma. This study demonstrated that long-term culture with imatinib mesylate, the tyrosine kinase inhibitor against PDGFR and c-Kit resulted in reduced cancer stem cell ability in glioblastoma cells through cell differentiation. Derived from RG glioblastoma cells co-cultured with imatinib for 3 months, RG-IM cells showed distinct properties of cell cycle distribution and morphology in addition to significantly decreased ability to form aggregates and colonies in vitro and tumorigenicity in vivo. Increased expression of GFAP (astrocyte marker) and class III β-tubulin isotype (Tuj1, neuron marker) were detected with morphology like neurons or astrocytes in RG-IM cells. Furthermore, decreased expression of stem cell markers, i.e., CD133, Oct-3/4, nestin, and Bmi1, and increased terminal neural cell markers, GFAP, Tuj1, etc., were identified in RG-IM at the mRNA level. All these markers were changed in RG cells when PDGFRB and c-Kit expression were double knocked down by siRNA. Cell differentiation agent, all-trans retinoic acid (ATRA) caused similar effect as that with imatinib in RG cells, while adding PDGF-B and SCF in RG-IM resulted in cell dedifferentiation to some extent. Moreover, differentiation in RG cells treated by imatinib or ATRA was mainly driven by MAPK signaling pathways. In summary, continuous inhibition on PDGFR and c-Kit signaling disturbed glioma stem cells biology in subsets of GBM cells and may have potentials in clinical applications.

Keywords

Glioblastoma multiforme Cancer stem cell Imatinib Cell differentiation MAPK 

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Yucui Dong
    • 1
    • 2
  • Qinglian Han
    • 1
    • 2
  • Yan Zou
    • 1
    • 2
  • Zhenling Deng
    • 1
    • 2
  • Xinliang Lu
    • 1
    • 2
  • Xiaohua Wang
    • 1
    • 2
  • Weihua Zhang
    • 3
  • Hua Jin
    • 4
  • Jun Su
    • 4
  • Tao Jiang
    • 5
  • Huan Ren
    • 1
    • 2
  1. 1.Department of ImmunologyHarbin Medical UniversityHarbinChina
  2. 2.Immunity & Infection Key Laboratory of Heilongjiang ProvinceHarbinChina
  3. 3.Department of PathophysiologyHarbin Medical UniversityHarbinChina
  4. 4.Department of NeurosurgeryThe Third Affiliated Hospital of Harbin Medical UniversityHarbinChina
  5. 5.Neurosurgery InstituteBeijing Tiantan HospitalBeijingChina

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