Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells.
We have examined microsatellite instability and loss of p53 function in human tumor cell line models of acquired anticancer drug resistance. We observe acquisition of an RER(+) phenotype in cell lines selected for resistance to cisplatin or doxorubicin. The majority of independent cisplatin-resistant sublines are RER(+), whereas the parental line shows no evidence of microsatellite instability. Microsatellite mutations in random, nonselected subclones of a cislatin-resistant line are observed in the absence of further drug exposure, suggesting that the RER(+) phenotype is a stable phenotype rather than being transiently induced by DNA damage. Furthermore, a cisplatin-resistant derivative shows reduction in a G:T mismatch recognition activity compared to the parental line. Independent lines selected by multiple exposure to cisplatin show resistance factors of up to a 5-fold by clonogenic assay and have reduced cisplatin-induced apoptosis. The resistant lines that are RER(+) show evidence of loss of p53-dependent functions, as measured by a loss of radiation-induced G(1) arrest and reduced CIP1 mRNA. Induced loss of p53 function by transfection of mutant TP53 does not cause a detectable RER(+) phenotype. We speculate that tolerance of DNA damage and expansion of cells with an RER(+) phenotype may select for reduced ability to engage apoptosis and loss of p53 function.
Anthoney
D A
DA
CRC Department of Medical Oncology, CRC Beatson Laboratories, Glasgow, United Kingdom.
McIlwrath
A J
AJ
Gallagher
W M
WM
Edlin
A R
AR
Brown
R
R
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004276:DNA, Satellite / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D007399:Interphase / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics; D010641:Phenotype; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004276:DNA, Satellite; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin