title: Activation of Aurora A kinase through the FGF1/FGFR signaling axis sustains the stem cell characteristics of glioblastoma cells.
abstract: Fibroblast growth factor 1 (FGF1) binds and activates FGF receptors, thereby regulating cell proliferation and neurogenesis. Human FGF1 gene 1B promoter (-540 to +31)-driven SV40 T antigen has been shown to result in tumorigenesis in the brains of transgenic mice. FGF1B promoter (-540 to +31)-driven green fluorescent protein (F1BGFP) has also been used in isolating neural stem cells (NSCs) with self-renewal and multipotency from developing and adult mouse brains. In this study, we provide six lines of evidence to demonstrate that FGF1/FGFR signaling is implicated in the expression of Aurora A (AurA) and the activation of its kinase domain (Thr288 phosphorylation) in the maintenance of glioblastoma (GBM) cells and NSCs. First, treatment of FGF1 increases AurA expression in human GBM cell lines. Second, using fluorescence-activated cell sorting, we observed that F1BGFP reporter facilitates the isolation of F1BGFP(+) GBM cells with higher expression levels of FGFR and AurA. Third, both FGFR inhibitor (SU5402) and AurA inhibitor (VX680) could down-regulate F1BGFP-dependent AurA activity. Fourth, inhibition of AurA activity by two different AurA inhibitors (VX680 and valproic acid) not only reduced neurosphere formation but also induced neuronal differentiation of F1BGFP(+) GBM cells. Fifth, flow cytometric analyses demonstrated that F1BGFP(+) GBM cells possessed different NSC cell surface markers. Finally, inhibition of AurA by VX680 reduced the neurosphere formation of different types of NSCs. Our results show that activation of AurA kinase through FGF1/FGFR signaling axis sustains the stem cell characteristics of GBM cells.
  
  
  
  This study identified a novel mechanism for the malignancy of GBM, which could be a potential therapeutic target for GBM.
authors.affiliation: Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan; Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan; Graduate Program of Biotechnology in Medicine, Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Kao
authors.affiliation: Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Chung
authors.affiliation: Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Don-Ching
authors.initials: DC
authors.lastname: Lee
authors.affiliation: Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Liu
authors.affiliation: Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan; Graduate Program of Biotechnology in Medicine, Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan. Electronic address: ingming@nhri.org.tw.
authors.forename: Ing-Ming
authors.initials: IM
authors.lastname: Chiu
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects; D002469:Cell Separation; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017930:Genes, Reporter; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064096:Aurora Kinase A; D016220:Fibroblast Growth Factor 1; D049452:Green Fluorescent Proteins; D010879:Piperazines; D017468:Receptors, Fibroblast Growth Factor; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
keywords: Aurora A; FGF1; Glioblastoma