CiteULike  View Full Text   View/Add Comment  Download reader    
Bo Cui,Stewart P. Johnson,Nancy Bullock,Francis Ali-Osman,Darell D. Bigner,Henry S. Friedman.Journal of Biomedical Research,2010,24(6):424-435
Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells
Received:August 25, 2010  
DOI10.1016/S1674-8301(10)60057-7
Keywordsglioblastomas multiforme, temozolomide, DNA damage response, resistance
Grant Program
                 
AuthorInstitution
Bo Cui Departments of Surgery, Duke University Medical Center, Durham, NC 22710, USA
Stewart P. Johnson Departments of Surgery, Duke University Medical Center, Durham, NC 22710, USA
Nancy Bullock Departments of Surgery, Duke University Medical Center, Durham, NC 22710, USA
Francis Ali-Osman Departments of Surgery, Duke University Medical Center, Durham, NC 22710, USA
Darell D. Bigner Departments of Pathology, Duke University Medical Center, Durham, NC 22710, USA
Henry S. Friedman Departments of Surgery, Duke University Medical Center, Durham, NC 22710, USA
Hits: 2076
Download times: 977
      
Abstract
      Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults. Current therapy includes surgery, radiation and chemotherapy with temozolomide (TMZ). Major determinants of clinical response to TMZ include methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter and mismatch repair (MMR) status. Though the MGMT promoter is methylated in 45% of cases, for the first nine months of follow-up, TMZ does not change survival outcome. Furthermore, MMR deficiency makes little contribution to clinical resistance, suggesting that there exist unrecognized mechanisms of resistance. We generated paired GBM cell lines whose resistance was attributed to neither MGMT nor MMR. We show that, responding to TMZ, these cells exhibit a decoupling of DNA damage response (DDR) from ongoing DNA damages. They display methyla-tion-resistant synthesis in which ongoing DNA synthesis is not inhibited. They are also defective in the activation of the S and G2 phase checkpoint. DDR proteins ATM, Chk2, MDC1, NBS1 and gammaH2AX also fail to form discrete foci. These results demonstrate that failure of DDR may play an active role in chemoresistance to TMZ. DNA damages by TMZ are repaired by MMR proteins in a futile, reiterative process, which activates DDR sign-aling network that ultimately leads to the onset of cell death. GBM cells may survive genetic insults in the absence of DDR. We anticipate that our findings will lead to more studies that seek to further define the role of DDR in ultimately determining the fate of a tumor cell in response to TMZ and other DNA methylators.
Close