Cisplatin-resistant HeLa cells are resistant to apoptosis via p53-dependent and -independent pathways.
Since HeLa cells possess very little functional p53 activity, they could be originally resistant to genotoxic stress-induced apoptosis. Therefore, it is likely that the drug-resistant cells derived from HeLa cells are more resistant to apoptosis. The aim of this study was to determine whether cisplatin-resistant cells derived from HeLa cells have an apoptosis-resistant phenotype. A cisplatin-resistant cell subline, HeLa/CDDP cells, showed a 19-fold resistance to cisplatin compared with the parent cells. The subline showed a collateral sensitivity to paclitaxel. An equitoxic dose (IC50) of cisplatin produced DNA fragmentation in HeLa cells but not in HeLa/CDDP cells. Transfection of wild-type p53 gene enhanced the cytotoxicity of cisplatin and cisplatin-induced apoptosis in HeLa cells but not in HeLa/CDDP cells, although it caused p53 overexpression in both cell lines. The expression of caspase 1 (interleukin-1beta-converting enzyme, ICE) mRNA and the overexpression of bax protein were observed only in HeLa cells. Paclitaxel-induced DNA fragmentation appeared less in HeLa/CDDP cells than in HeLa cells. p53 gene transfection did not affect the extent of DNA fragmentation in either cell line, suggesting that paclitaxel may induce p53-independent apoptosis. These findings suggest that HeLa/CDDP cells may have an acquired phenotype that is resistant to p53-dependent and -independent apoptosis.
Minagawa
Y
Y
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago. kigawa@grape.med.tottori-u.ac.jp
Kigawa
J
J
Itamochi
H
H
Kanamori
Y
Y
Shimada
M
M
Takahashi
M
M
Terakawa
N
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells / Q000187:drug effects*; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel; D002945:Cisplatin