title: Msh2 deficiency does not contribute to cisplatin resistance in mouse embryonic stem cells.
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.
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Nanna
authors.initials: N
authors.lastname: Claij
authors.forename: Hein
authors.initials: H
authors.lastname: te Riele
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004351:Drug Resistance; D004622:Embryo, Mammalian / Q000166:cytology*; D019426:Integrases / Q000502:physiology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000502:physiology; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects*; D014764:Viral Proteins / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014764:Viral Proteins; D008769:Methylnitronitrosoguanidine; C045073:Cre recombinase; D019426:Integrases; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002945:Cisplatin