TY - JOUR
T1 - Differential sensitivity of glioma stem cells to aurora kinase A inhibitors
T2 - implications for stem cell mitosis and centrosome dynamics
AU - Mannino, Mariella
AU - Gomez-Roman, Natividad
AU - Hochegger, Helfrid
AU - Chalmers, Anthony J.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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.
KW - aurora kinase A inhibitor
KW - enzyme inhibitor
KW - polo like kinase 1
KW - azepine derivative
KW - protein kinase inhibitor
KW - asymmetric cell division
KW - cell differentiation
UR - http://www.scopus.com/inward/record.url?scp=84901456358&partnerID=8YFLogxK
U2 - 10.1016/j.scr.2014.05.001
DO - 10.1016/j.scr.2014.05.001
M3 - Article
C2 - 24879067
AN - SCOPUS:84901456358
SN - 1873-5061
VL - 13
SP - 135
EP - 143
JO - Stem Cell Research
JF - Stem Cell Research
IS - 1
ER -