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

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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.

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Acknowledgments

The presented research project was supported by the Key Project Science Foundation of Heilongjiang Province, China (Grant-ZD200804-01), Chinese Postdoctoral Fellowship (Grant-2008043938), and National Science Foundation of China (Grant NFSC-30227738), to Huan Ren.

Conflict of interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Immunology, Harbin Medical University, 157 Baojian Road, 150081, Harbin, China

    Yucui Dong, Qinglian Han, Yan Zou, Zhenling Deng, Xinliang Lu, Xiaohua Wang & Huan Ren

  2. Immunity & Infection Key Laboratory of Heilongjiang Province, 150081, Harbin, China

    Yucui Dong, Qinglian Han, Yan Zou, Zhenling Deng, Xinliang Lu, Xiaohua Wang & Huan Ren

  3. Department of Pathophysiology, Harbin Medical University, 150081, Harbin, China

    Weihua Zhang

  4. Department of Neurosurgery, The Third Affiliated Hospital of Harbin Medical University, 150081, Harbin, China

    Hua Jin & Jun Su

  5. Neurosurgery Institute, Beijing Tiantan Hospital, 100005, Beijing, China

    Tao Jiang

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  1. Yucui Dong
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Correspondence to Huan Ren.

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Dong, Y., Han, Q., Zou, Y. et al. Long-term exposure to imatinib reduced cancer stem cell ability through induction of cell differentiation via activation of MAPK signaling in glioblastoma cells. Mol Cell Biochem 370, 89–102 (2012). https://doi.org/10.1007/s11010-012-1401-0

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  • DOI: https://doi.org/10.1007/s11010-012-1401-0

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