WAF1/CIP1 increases the susceptibility of p53 non-functional malignant glioma cells to cisplatin-induced apoptosis.
Induction of apoptosis in tumor cells is an important determinant in the outcome of therapy. Molecular details of the apoptosis pathway, however, are still poorly defined. The recently discovered WAF1/CIP1 gene is a potent inhibitor of cyclin-dependent kinases and a mediator of tumor-suppressor p53-dependent apoptosis by DNA damage. In addition, WAF1/CIP1 expression is shown to be triggered through the p53-independent pathway. The relationship between WAF1/CIP1 and p53-independent apoptosis by DNA damage, however, remains unclear. In this study, we show that WAF1/CIP1 was induced in p53-dependent apoptosis of U87-MG glioma cells by cis-diamminedichloroplatinum (cisplatin), and overexpression of WAF1/CIP1 induced apoptosis in U87-MG cells without cisplatin treatment. In contrast, the p53-independent apoptosis of GB-1 glioma cells by cisplatin did not express WAF1/CIP1. Overexpression of WAF1/CIP1 inhibited DNA synthesis in GB-1 cells, but did not induce apoptosis. Interestingly, WAF1/CIP1 increased the susceptibility of GB-1 cells to cisplatin-induced apoptosis. These results suggest that overexpression of WAF1/CIP1 may have potential for the treatment of tumors with non-functional p53.
Kondo
S
S
Department of Neurosurgery, Brain Tumor Center/Cancer Center, The Cleveland Clinic Foundation, Ohio 44195, USA.
Barna
B P
BP
Kondo
Y
Y
Tanaka
Y
Y
Casey
G
G
Liu
J
J
Morimura
T
T
Kaakaji
R
R
Peterson
J W
JW
Werbel
B
B
Barnett
G H
GH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D016158:Genes, p53; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin