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  • Original Paper
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Inactivated MGMT by O6-Benzylguanine is associated with prolonged G2/M arrest in cancer cells treated with BCNU

Oncogene volume 24, pages 2175–2183 (2005)Cite this article

Abstract

HCT116 and HCT15 cells that highly express O6-methylguanine-DNA-methyltransferase (MGMT) displayed a transient cell cycle G2/M arrest in response to exposure to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) alone; however, 70–80% of cells were arrested in G2/M after treatment with O6-benzylguanine (BG) and BCNU. Cells accumulated in G2/M showed elevated levels of an inactive form of cyclin B1/p-Cdc2 (Tyr15) complex that was not associated with activation of Chk1/p-Cdc25C and was independent of p53/p21 status. The most prominent feature of cell death was the appearance of enlarged and multinucleated cells that was related to the inhibition of mitotic entry. In contrast, BG-resistant cell lines, HCT116 BBR and HCT15 BBR cells that contain mutations K165E and K165N of MGMT, respectively, displayed a normal cell cycle progression with a slight and transient increase in G2/M arrest at 24 h after treatments with either BCNU alone or BG combined with BCNU. The differences in the ability to progress toward G2/M after treatment with BG and BCNU between cells expressing wild-type MGMT and mutated MGMT were confirmed in CHO cells transfected with human wild type and K165E mutant MGMT cDNA, respectively. Thus, our findings suggest that BG-inactivated MGMT may be linked to cell signaling events, forcing cells into a permanent G2/M arrest in response to the DNA damages induced by BCNU.

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Acknowledgements

We thank Dr Stanton L Gerson for providing Vaco 8/MGMT cells and for helpful discussions. This work was supported by Public Health Service Grants RO1CA82292.

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  1. Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    Ling Yan, Jon R Donze & Lili Liu

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Correspondence to Lili Liu.

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Yan, L., Donze, J. & Liu, L. Inactivated MGMT by O6-Benzylguanine is associated with prolonged G2/M arrest in cancer cells treated with BCNU. Oncogene 24, 2175–2183 (2005). https://doi.org/10.1038/sj.onc.1208250

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