title: Long-term exposure to imatinib reduced cancer stem cell ability through induction of cell differentiation via activation of MAPK signaling in glioblastoma cells.
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.
authors: Department of Immunology, Harbin Medical University, Harbin, China.
authors: Yucui
authors: Y
authors: Dong
authors: Qinglian
authors: Q
authors: Han
authors: Yan
authors: Y
authors: Zou
authors: Zhenling
authors: Z
authors: Deng
authors: Xinliang
authors: X
authors: Lu
authors: Xiaohua
authors: X
authors: Wang
authors: Weihua
authors: W
authors: Zhang
authors: Hua
authors: H
authors: Jin
authors: Jun
authors: J
authors: Su
authors: Tao
authors: T
authors: Jiang
authors: Huan
authors: H
authors: Ren
mesh_terms: D000818:Animals; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor