A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells

Lim, Yi Chieh, Roberts, Tara L., Day, Bryan W., Harding, Angus, Kozlov, Sergei, Kijas, Amanda W., Ensbey, Kathleen S., Walker, David G. and Lavin, Martin F. (2012) A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells. Molecular Cancer Therapeutics, 11 9: 1863-1872.


Author Lim, Yi Chieh
Roberts, Tara L.
Day, Bryan W.
Harding, Angus
Kozlov, Sergei
Kijas, Amanda W.
Ensbey, Kathleen S.
Walker, David G.
Lavin, Martin F.
Title A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells
Journal name Molecular Cancer Therapeutics  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2012-09
Sub-type Article
DOI 10.1158/1535-7163.MCT-11-1044
Volume number 11
Issue number 9
ISSN 1535-7163
1538-8514
Start page 1863
End page 1872
Total pages 10
Place of publication Philadelphia, PA, U.S.A.
Publisher American Association for Cancer Research
Collection year 2013
Language eng
Abstract Glioblastoma multiforme (GBM) is the most common form of brain tumor with a poor prognosis and resistance to radiotherapy. Recent evidence suggests that glioma-initiating cells play a central role in radio resistance through DNA damage checkpoint activation and enhanced DNA repair. To investigate this inmore detail, we compared the DNA damage response in nontumor forming neural progenitor cells (NPC) and glioma-initiating cells isolated from GBM patient specimens. As observed for GBM tumors, initial characterization showed that glioma-initiating cells have long-term self-renewal capacity. They express markers identical toNPCs and have the ability to form tumors in an animal model. In addition, these cells are radioresistant to varying degrees, which could not be explained by enhanced nonhomologous end joining (NHEJ). Indeed, NHEJ in glioma-initiating cells was equivalent, or in some cases reduced, as compared with NPCs. However, there was evidence for more efficient homologous recombination repair in glioma-initiating cells. We did not observe a prolonged cell cycle nor enhanced basal activation of checkpoint proteins as reported previously. Rather, cell-cycle defects in the G1-S and S-phase checkpoints were observed by determining entry into S-phase and radioresistant DNA synthesis following irradiation. These data suggest that homologous recombination and cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and that both processes may be suitable targets for therapy.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Mon, 19 Nov 2012, 08:20:05 EST by Matthew Lamb on behalf of School of Medicine