Minagawa Y, Kigawa J, Itamochi H, Kanamori Y, Shimada M, Takahashi M, Terakawa N
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago.
Jpn J Cancer Res. 1999 Dec;90(12):1373-9. doi: 10.1111/j.1349-7006.1999.tb00722.x.
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.
由于HeLa细胞具有极低的功能性p53活性，它们最初可能对基因毒性应激诱导的凋亡具有抗性。因此，源自HeLa细胞的耐药细胞可能对凋亡更具抗性。本研究的目的是确定源自HeLa细胞的顺铂耐药细胞是否具有抗凋亡表型。一个顺铂耐药细胞亚系HeLa/CDDP细胞，与亲本细胞相比，对顺铂表现出19倍的抗性。该亚系对紫杉醇表现出协同敏感性。等毒性剂量（IC50）的顺铂在HeLa细胞中产生DNA片段化，但在HeLa/CDDP细胞中未产生。野生型p53基因的转染增强了顺铂对HeLa细胞的细胞毒性和顺铂诱导的凋亡，但对HeLa/CDDP细胞没有作用，尽管它在两种细胞系中都导致了p53的过表达。仅在HeLa细胞中观察到半胱天冬酶1（白细胞介素-1β转换酶，ICE）mRNA的表达和bax蛋白的过表达。HeLa/CDDP细胞中紫杉醇诱导的DNA片段化比HeLa细胞中少。p53基因转染对两种细胞系中的DNA片段化程度均无影响，这表明紫杉醇可能诱导不依赖p53的凋亡。这些发现表明，HeLa/CDDP细胞可能获得了一种对p53依赖性和非依赖性凋亡均具有抗性的表型。
