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Mol Cancer Res ; 7(2): 237-46, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19208740

RESUMO

The p53 protein is a key regulator of cell responses to DNA damage, and it has been shown that it sensitizes glioma cells to the alkylating agent temozolomide by up-regulating the extrinsic apoptotic pathway, whereas it increases the resistance to chloroethylating agents, such as ACNU and BCNU, probably by enhancing the efficiency of DNA repair. However, because these agents induce a wide variety of distinct DNA lesions, the direct importance of DNA repair is hard to access. Here, it is shown that the induction of photoproducts by UV light (UV-C) significantly induces apoptosis in a p53-mutated glioma background. This is caused by a reduced level of photoproduct repair, resulting in the persistence of DNA lesions in p53-mutated glioma cells. UV-C-induced apoptosis in p53 mutant glioma cells is preceded by strong transcription and replication inhibition due to blockage by unrepaired photolesions. Moreover, the results indicate that UV-C-induced apoptosis of p53 mutant glioma cells is executed through the intrinsic apoptotic pathway, with Bcl-2 degradation and sustained Bax and Bak up-regulation. Collectively, the data indicate that unrepaired DNA lesions induce apoptosis in p53 mutant gliomas despite the resistance of these gliomas to temozolomide, suggesting that efficiency of treatment of p53 mutant gliomas might be higher with agents that induce the formation of DNA lesions whose global genomic repair is dependent on p53.


Assuntos
Apoptose/efeitos da radiação , Neoplasias Encefálicas/patologia , Glioma/patologia , Mutação/genética , Dímeros de Pirimidina , Proteína Supressora de Tumor p53/genética , Raios Ultravioleta , Apoptose/genética , Neoplasias Encefálicas/metabolismo , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Replicação do DNA/efeitos dos fármacos , Replicação do DNA/efeitos da radiação , Proteína de Domínio de Morte Associada a Fas/metabolismo , Citometria de Fluxo , Glioma/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Neoplásico/genética , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/efeitos da radiação , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
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