Inactivation of p53 sensitizes U87MG glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea.
We examined the effect of p53 inactivation on the response of U87MG glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These studies were motivated by three observations: (a) some human astrocytomas are sensitive to BCNU and some are resistant; (b) chemosensitive astrocytomas are more likely to be found in young adults whose tumors are more likely to harbor a p53 mutation; and (c) mouse astrocytes lacking the p53 gene are more sensitive to BCNU than wild-type cells. Here, we observed that p53 inactivation by transfection with pCMV-E6 sensitized U87MG cells to BCNU. Compared with control U87MG-neo cells with intact p53 function, the clonogenic survival of U87MG-E6 cells exposed to BCNU was reduced significantly. In U87MG-E6 cells, sensitization to BCNU was associated with failure of p21(WAF1) induction, transient cell cycle arrest in S phase, accumulation of polyploid cells, and significant cell death. In contrast, resistance to BCNU in U87MG-neo cells was associated with up-regulation of p53, prolonged induction of p21(WAF1), sustained cell cycle arrest in S phase, and enhancement of DNA repair. U87MG cells with disrupted p53 function were less able to repair BCNU-induced DNA damage and survive this chemotherapeutic insult. The question arises of whether p53 dysfunction might be a chemosensitizing genetic alteration in human astrocytic gliomas.
Xu
G W
GW
Department of Oncology, University of Western Ontario, London Regional Cancer Centre, 790 Commissioners Road East, London, Ontario, N6A 4L6 Canada.
Nutt
C L
CL
Zlatescu
M C
MC
Keeney
M
M
Chin-Yee
I
I
Cairncross
J G
JG
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004260:DNA Repair / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D018906:Antineoplastic Agents, Alkylating; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D002330:Carmustine