Prostate cancer cell cycle regulators: Response to androgen withdrawal and development of androgen independence
Prostate cancer cell cycle regulators: Response to androgen withdrawal and development of androgen independence
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DOI：
10.1093/jnci/91.21.1869
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发表时间：
1999-11-03
期刊：
影响因子：
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通讯作者：
Scher, HI
中科院分区：
文献类型：
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作者：
Agus, DB;Cordon-Cardo, C;Scher, HI
背景资料：雄激素戒断是前列腺癌的标准疗法，可导致大多数患者肿瘤体积缩小和血清前列腺特异性抗原下降。为了了解与雄激素戒断后前列腺癌消退相关的因素，我们研究了CWR 22人前列腺癌异种移植模型中细胞周期调节因子的变化。研究方法：在雄激素戒断后和雄激素非依赖性发展后的不同时间对裸无胸腺BALB/c小鼠中建立的肿瘤进行取样。细胞周期调节因子表达的变化分为早期和中期至晚期事件。结果和结论：早期事件包括雄激素受体表达减少，随后是p53和p21/WAF 1蛋白表达的短期增加和Ki 67增殖指数的显著降低。中晚期事件包括p27和p16蛋白表达的进行性和持续性增加，视网膜母细胞瘤蛋白表达的减少和转录因子E2 F1的增加。在雄激素戒断后的任何时间都没有观察到细胞凋亡（程序性细胞死亡）的变化。这些数据表明，雄激素戒断导致细胞应激反应，其中增加的p53蛋白产生细胞周期停滞，而不激活p53介导的凋亡。通过细胞周期蛋白依赖性激酶抑制剂p27和p16的作用，增殖指数进一步降低。在雄激素撤除后80-400天出现雄激素非依赖性亚系，这些亚系具有不同的生长表型，但与mdm 2蛋白过表达和细胞周期蛋白D1表达增加相关，这些结果表明，在这种人前列腺癌模型中，肿瘤消退是由于细胞周期停滞而不是凋亡，雄激素非依赖性的出现与细胞周期的释放有关逮捕了
Background: Androgen withdrawal is a standard therapy for prostate cancer that results in a decrease in tumor volume and a decline in serum prostate-specific antigen in the majority of patients. To understand the factors associated with regression of prostate cancers after androgen withdrawal, we studied cell cycle regulator changes in the CWR22 human prostate cancer xenograft model. Methods: Established tumors in nude athymic BALB/c mice were sampled at various times after androgen withdrawal and after the development of androgen independence. Changes in the expression of cell cycle regulators were categorized into early and mid-to-late events. Results and Conclusions: Early events included a decrease in androgen receptor expression, followed by a short-term increase in expression of the p53 and p21/WAF1 proteins and a marked decrease in the Ki67 proliferative index. Mid-to-late events included progressive and sustained increases in p27 and p16 protein expression, a decrease in retinoblastoma protein expression, and an increase in the transcription factor E2F1. Changes in apoptosis (programmed cell death) were not observed at any time after androgen withdrawal. These data suggest that androgen withdrawal results in a cell stress response, in which increased p53 protein produces a cell cycle arrest, without activation of p53-mediated apoptosis, The proliferative index is further decreased through the action of the cyclin-dependent kinase inhibitors p27 and p16. Androgen-independent sublines emerged 80-400 days after androgen withdrawal, and these sublines had variable growth phenotypes but were associated with mdm2 protein overexpression and increased expression of cyclin D1, These results indicate that tumor regression in this human prostate cancer model is due to cell cycle arrest rather than to apoptosis and that the emergence of androgen independence is associated with a release from cell cycle arrest.