Induction of p53-mediated apoptosis and recovery of chemosensitivity through p53 transduction in human glioblastoma cells by cisplatin.
Cisplatin is a DNA-damaging chemotherapeutic drug that may have a role in the adjuvant chemotherapy of several solid tumors, such as malignant glioblastoma, and the status of p53 tumor suppressor protein is a critical determinant of cisplatin chemosensitivity. In the present study, we showed the relationship of p53 status and chemosensitivity of cisplatin between two human malignant glioblastoma cell lines, A172 and T98G, harboring wild-type and mutant-type p53, respectively. Cisplatin was found to be more cytotoxic to A172 than T98G cells in a time- and concentration-dependent manner. Cisplatin-induced cytotoxicity manifested as apoptosis, characterized by genomic DNA fragmentation, nuclear condensation and an increase in sub-G1 population. Cisplatin induced the accumulation of p53 and p21 proteins in A172 cells, but not in T98G cells. The introduction of the adenovirus-mediated wild-type p53 gene into T98G cells resulted in the decrease of viability as well as the increase in sub-G1 population with p53 accumulation, activation of caspase-3 protease and release of cytochrome c from the mitochondria. These data strongly suggest that the expression of p53 is essential for the cytotoxic effect of cisplatin in human malignant glioblastoma cells, A172 and T98G, and the introduction of apoptotic signal molecules, such as p53, will be beneficial to achieve chemosensitivity in malignant glioma.
Park
Chang-Min
CM
Laboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Park
Myung-Jin
MJ
Kwak
Hee-Jin
HJ
Moon
Sang-Ik
SI
Yoo
Doo-Hyun
DH
Lee
Hyung-Chahn
HC
Park
In-Chul
IC
Rhee
Chang Hun
CH
Hong
Seok-Il
SI
D017209:Apoptosis; D001932:Brain Neoplasms / Q000473:pathology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D016158:Genes, p53; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000502:physiology
D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin