title: Differential sensitivity of Glioma stem cells to Aurora kinase A inhibitors: implications for stem cell mitosis and centrosome dynamics.
abstract: Glioma stem-cell-like cells are considered to be responsible for treatment resistance and tumour recurrence following chemo-radiation in glioblastoma patients, but specific targets by which to kill the cancer stem cell population remain elusive. A characteristic feature of stem cells is their ability to undergo both symmetric and asymmetric cell divisions. In this study we have analysed specific features of glioma stem cell mitosis. We found that glioma stem cells appear to be highly prone to undergo aberrant cell division and polyploidization. Moreover, we discovered a pronounced change in the dynamic of mitotic centrosome maturation in these cells. Accordingly, glioma stem cell survival appeared to be strongly dependent on Aurora A activity. Unlike differentiated cells, glioma stem cells responded to moderate Aurora A inhibition with spindle defects, polyploidization and a dramatic increase in cellular senescence, and were selectively sensitive to Aurora A and Plk1 inhibitor treatment. Our study proposes inhibition of centrosomal kinases as a novel strategy to selectively target glioma stem cells.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN19RQ, UK.
authors.forename: Mariella
authors.initials: M
authors.lastname: Mannino
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Natividad
authors.initials: N
authors.lastname: Gomez-Roman
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN19RQ, UK. Electronic address: h.hochegger@sussex.ac.uk.
authors.forename: Helfrid
authors.initials: H
authors.lastname: Hochegger
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: anthony.chalmers@glasgow.ac.uk.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chalmers
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A