Prolonged wild-type p53 protein accumulation and cisplatin resistance.
The major limitation for the chemotherapeutic use of DNA-damaging agent cisplatin is the development of resistance in initially responsive tumors. One of the main pathways regulating cell survival following DNA damage is the p53 pathway. In this study we compared the cisplatin-induced response of p53 protein and its downstream targets p21WAF-1 and Mdm2 in the cisplatin-sensitive ovarian carcinoma cell line A2780 and its cisplatin-resistant derivative CP70. A higher dose of cisplatin and a longer exposure time was required to achieve the same level of p53, p21WAF-1, and Mdm2 protein accumulation in the cisplatin-resistant CP70 cells versus cisplatin-sensitive A2780 cells. A significant difference between the two cell lines was observed in cisplatin-induced stabilization of p53 protein. The p53 half-life increased 31-fold in CP70 cells compared to only 6-fold in A2780 cells. In contrast, there was no difference in p21WAF-1 half-life between the two cell lines. These results demonstrate that in A2780 and CP70 cells resistance to cisplatin correlates with prolonged p53 protein stabilization and accumulation.
Yazlovitskaya
E M
EM
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA.
DeHaan
R D
RD
Persons
D L
DL
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin