Transcriptional repression of O6-methylguanine DNA methyltransferase gene rendering cells hypersensitive to N,N′-Bis(2- chloroethyl)-N-nitrosurea in camptothecin-resistant cells

Li Chen Ma, Ching Chuan Kuo, Jin Fen Liu, Li Tzong Chen, Jang Yang Chang

研究成果: Article同行評審

5 引文 斯高帕斯(Scopus)

摘要

O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein t0hat removes alkyl-adducts from the O6-guanine in DNA and is a crucial defense against O6-alkylating agentinduced cytotoxicity. We demonstrated here that two camptothecin (CPT)-resistant cell lines (CPT30 and KB100) were more sensitive to N,N′-bis(2-chloroethyl)-N-nitrosurea (BCNU) than their parental cells. Enhanced sensitivity to BCNU in these two CPT-resistant cells involved transcriptional repression of the MGMT gene. The mechanism of MGMT gene down-regulation in CPT-resistant cells was not through gene abnormality, mRNA stability, and CpG island hypermethylation. However, the high level of methyl-CpG-binding protein 2 (MeCP2) and dimethylation of H3K9 in the promoter region were found in CPT30 and KB100 cells. Furthermore, increased MeCP2 binding on MGMT promoter was also found to be correlated with MGMT genesilencing in short-term CPT treatment; thus, enhanced BCNU sensitivity was found in CPT-treated cells. Taken together, we suggest that CPT is able to suppress the transcription of the MGMT gene through recruiting of MeCP2 and H3K9 dimethy-lation, thus causing a synergistic interaction with BCNU. These findings provide a possible explanation regarding why the combination of CPT and BCNU results in a better objective response than single-use alone. In addition, this study supports a new indication for treating patients who are receiving refractory CPT derivatives with BCNU.

原文English
頁(從 - 到)517-526
頁數10
期刊Molecular Pharmacology
74
發行號2
DOIs
出版狀態Published - 2008 八月 1

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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