Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells.
We investigated the p53 status and the ability of exogenous wildtype (wt) p53 to affect chemosensitivity in three anaplastic thyroid carcinoma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not result in accumulation of p53 or induction of p21WAF1/CIP1 or Mdm-2 and did not cause Rb dephosphorylation. BHT-101 and KAT-4 cells had mutant p53. SW-1736 cells were functionally mutant because of marked down-regulation of wt p53 messenger ribonucleic acid, representing a novel mechanism of p53 dysfunction. Infection with a p53-expressing adenovirus (Ad-p53) induced high levels of p21 and Mdm-2 proteins. In BHT-101 cells, induction of p21 and Mdm-2 was evident 10 h after infection. In KAT-4 cells, induction of p21 and Mdm-2 was observed 1 day after infection, and continued to increase over the ensuing 24 h. SW-1736 cells demonstrated intermediate kinetics. Sensitivity to the cytotoxic effect of Ad-p53 paralleled the kinetics of p21/Mdm-2 induction. BHT-101 cells were most sensitive to killing by Ad-p53, with an IC50 of less than 2 multiplicity of infection; SW-1736 cells were intermediate in sensitivity; KAT-4 cells were resistant. All three cell lines became more sensitive to adriamycin after wt p53 expression, with a 10-fold decrease in IC50 values. The latter observation may make a combination of wt p53 and chemotherapeutic drugs an attractive modality for treating anaplastic thyroid cancer.
Blagosklonny
M V
MV
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Giannakakou
P
P
Wojtowicz
M
M
Romanova
L Y
LY
Ain
K B
KB
Bates
S E
SE
Fojo
T
T
D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000821:virology; D002454:Cell Differentiation / Q000502:physiology; D002945:Cisplatin / Q000627:therapeutic use; D004249:DNA Damage; D004317:Doxorubicin / Q000627:therapeutic use; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D007700:Kinetics; D007763:Lac Operon; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004317:Doxorubicin; D002945:Cisplatin