MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis.
Induction of apoptosis in tumor cells is an important mechanism of chemotherapy-induced cell death. The tumor-suppressor gene p53 is required for the efficient activation of apoptosis following chemotherapy. However, the molecular mechanism regulating p53-associated apoptosis remains controversial. In this study, we show that the expression of both wild-type p53 and MDM2 (murine double minute 2) proteins was induced when cis-diamminedichloroplatinum (cisplatin) caused apoptosis in human glioblastoma U87-MG cells, which expressed neither wild-type p53 nor MDM2 protein prior to treatment. Overexpression of MDM2 in U87-MG cells transfected with human mdm2 expression vector conferred the resistance of tumor cell to cisplatin-induced apoptosis. In contrast, the treatment with mdm2 antisense oligonucleotide targeted against mdm2 mRNA increased the susceptibility of tumor cells to apoptosis. Changes in expression level of MDM2 protein, however, did not affect the expression of wild-type p53 protein. These findings suggest that MDM2 protein may act as a negative regulator of cisplatin-induced apoptosis, and moreover, may play an important role in the development of resistance to cisplatin in human tumors.
Kondo
S
S
Department of Neurosurgery, Cleveland Clinic Foundation, OH 44195, USA.
Barnett
G H
GH
Hara
H
H
Morimura
T
T
Takeuchi
J
J
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000378:metabolism; 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 / Q000378:metabolism*
D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin