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Msh2 deficiency does not contribute to cisplatin resistance in mouse embryonic stem cells

Oncogene volume 23, pages 260–266 (2004)Cite this article

Abstract

Several reports have suggested that a defect in the DNA mismatch repair (MMR) system not only causes resistance to methylating agents but also confers low-level resistance to the chemotherapeutic drug cisplatin. Here we report that in a clonogenic assay, mouse embryonic stem (ES) cells deficient for the MMR protein MSH2 respond similarly as wild-type cells to cisplatin. Furthermore, restoring MSH2 expression in a cisplatin-resistant subclone selected from an Msh2−/− cell population did not sensitize cells to cisplatin. To ascertain that our observations were not the result of a mutation in the Msh2−/− cells that obscured the contribution of a defective MMR machinery to cisplatin resistance, we made use of the Cre-lox system to create a cell line in which the Msh2 gene can be conditionally inactivated. However, while de novo inactivation of Msh2 rendered cells tolerant to the methylating drug N-methyl-N′-nitro-N-nitrosoguanidine as expected, it did not alter the sensitivity to cisplatin. In addition, we were not able to derive cisplatin-resistant subclones from this freshly generated MMR-deficient cell line. Thus, in ES cells we did not find evidence for direct involvement of MMR deficiency in cisplatin resistance.

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Acknowledgements

We thank Judith Martens for cloning the loxP site downstream of exon 13, Valerie Doodeman and Yvonne van Klink for technical assistance, Jos Jonkers for providing us with CMV-Cre, loxP and floxed Neo plasmids, R Moschel for the gift of O6-benzylguanine, and Marjolein Sonneveld for helpful comments on the manuscript. We acknowledge support from the Dutch Cancer Society (Grant NKI 98-1838) and the European Committee (Grant ENV4-CT97-0469).

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  1. Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Nanna Claij & Hein te Riele

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  1. Nanna Claij
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Correspondence to Hein te Riele.

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Claij, N., te Riele, H. Msh2 deficiency does not contribute to cisplatin resistance in mouse embryonic stem cells. Oncogene 23, 260–266 (2004). https://doi.org/10.1038/sj.onc.1207015

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