Cisplatin‐resistant HeLa Cells Are Resistant to Apoptosis via p53‐dependent and ‐independent Pathways

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Abstract
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 p53gene 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‐1β‐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. p53gene 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.