Loss of p73 induction in a cisplatin-resistant bladder cancer cell line.
BACKGROUND
Cisplatin (CDDP) plays an important role in the treatment of transitional-cell carcinoma (TCC), but resistance develops. The mechanism is not entirely understood.


METHODS
To assess acquired resistance to CDDP, we established a CDDP-resistant subclone, CL8-2, of T24, which is a bladder cancer cell line. We examined the changes in the various pathways leading to apoptosis in the parent line and CL8-2.


RESULTS
The drug caused apoptosis of T24 cells but not CL8-2 cells. The CL8-2 cells were 6.4 times more resistant to CDDP than was T24. In both cell lines, the mismatch repair genes hMLH-1 and hMSH-2 were expressed at high levels. The p53 protein was not detected in either cell line but p73 protein was induced by CDDP treatment in T24 cells, which was followed by activation of caspases 3, 8, and 9. This phenomenon was not observed in CL8-2 cells.


CONCLUSIONS
These results suggest that loss of p73 induction may lead to CDDP resistance of TCC.
Ono
Y
Y
Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
Nonomura
N
N
Harada
Y
Y
Fukui
T
T
Tokizane
T
T
Sato
E
E
Nakayama
M
M
Nishimura
K
K
Takahara
S
S
Okuyama
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis; D002945:Cisplatin / Q000494:pharmacology*; D002999:Clone Cells; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis*; D004351:Drug Resistance; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000032:analysis*; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020741:rho GTP-Binding Proteins; D002945:Cisplatin