p53-dependent and -independent responses to cisplatin in mouse testicular teratocarcinoma cells

Testicular cancers respond favorably to chemotherapy with the platinum-containing drug cis-diamminedichloroplatinum(II) (cisplatin). One factor that could explain the efficacy of cisplatin is the low frequency of p53 mutations observed in this tumor type. The present study examines the p53-mediated responses in murine testicular teratocarcinoma cells exposed to the drug. Cisplatin treatment of teratocarcinoma cells with a wild-type p53 gene resulted in accumulation of the p53 protein through posttranscriptional mechanisms; induction of p53-target genes was also observed. Drug treatment resulted in rapid apoptosis in p53-wild-type cells but not in p53(−/−) teratocarcinoma cells. In the latter cells, cisplatin exposure caused prolonged cell cycle arrest accompanied by induction of the p21 gene. Clonogenic assays demonstrated that the p53 mutation did not confer resistance to cisplatin. These experiments suggest that cisplatin inhibits cellular proliferation of testicular teratocarcinoma cells by two possible mechanisms, p53-dependent apoptosis and p53-independent cell cycle arrest.

睾丸癌对含铂药物顺铂（cis-diamminedichloroplatinum(II)，cisplatin）的化疗应答效果良好。可解释顺铂疗效的一项关键因素为，该肿瘤类型中观测到的p53突变频率较低。本研究针对暴露于该药物的小鼠睾丸畸胎瘤细胞，探究了p53介导的细胞应答反应。对携带野生型p53基因的畸胎瘤细胞施以顺铂处理，可通过转录后机制促使p53蛋白积累，同时还可观测到p53靶基因的诱导表达。药物处理可使野生型p53细胞快速发生细胞凋亡，而p53基因敲除（p53(−/−)）的畸胎瘤细胞则未出现该现象。在后者细胞中，顺铂暴露会引发长时间的细胞周期阻滞，并伴随p21基因的诱导表达。集落形成实验结果表明，p53突变并未赋予细胞对顺铂的耐药性。本实验提示，顺铂可通过两种潜在机制抑制睾丸畸胎瘤细胞的增殖：p53依赖性细胞凋亡，以及p53非依赖性细胞周期阻滞。