Mdm2 sensitizes MCF7 breast cancer cells to cisplatin or carboplatin.
Overexpression of Mdm2 in cancer cells with otherwise wild-type p53 is believed to be an alternative mechanism for p53 inactivation during carcinogenesis. Because a number of genetic alterations that inactivate p53, including mutation, homozygous deletion, or viral oncoprotein expression (e.g. HPV16-E6), inhibit DNA repair, we tested the hypothesis that Mdm2 would likewise inhibit DNA repair. Repair of cisplatin-induced DNA damage was reduced in MCF7 cells overexpressing Mdm2, compared to MCF7 cells in which wild-type p53 function was intact. MCF7-Mdm2 cells exhibited preferential sensitivity to cisplatin and carboplatin. MCF7-Mdm2 cells showed a pronounced S-phase arrest after cisplatin treatment, similar to that observed in mutant-p53 cells in the present and prior studies. MCF7 cells with intact wild-type p53, on the other hand, arrested primarily in G2/M phase after cisplatin treatment. These findings indicate that Mdm2 overexpression can recapitulate the effect of p53 mutations on DNA repair of cisplatin lesions.
Smith
M L
ML
Indiana University Cancer Center, Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, USA. marlsmit@iupui.edu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D016190:Carboplatin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D016190:Carboplatin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin