Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Semin Radiat Oncol. 2010 Oct;20(4):258-66. doi: 10.1016/j.semradonc.2010.05.007.
Both the p53- and E2F1-signaling pathways are defective in almost all types of tumors, suggesting very important roles for their signaling networks in regulating the process of tumorigenesis and therapy response. Studies on Radiation Therapy Oncology Group tissue samples have identified aberrant expression of p53, MDM2 (an E3 ubiquitin ligase that targets p53 for proteosomal degradation), and p16 (an upstream regulator of retinoblastoma and hence E2F1 in prostate cancer); abnormal expression of these biomarkers has been associated with clinical outcome after radiotherapy ± androgen deprivation therapy. Although the proapoptotic properties of p53 are well documented, a relatively new aspect of p53 function as an active mediator of prosurvival signaling pathways is now emerging. E2F1 is a transcription factor that possesses both proapoptotic and prosurvival properties. Thus, the role of E2F1 in the process of tumorigenesis versus apoptosis is a contested issue that needs to be resolved. Furthermore, the role of E2F1 in DNA repair is being increasingly recognized. Thus, novel approaches to curb the prosurvival and DNA repair capability of E2F1 while promoting apoptotic function are of interest. In this review, we discuss the challenges involved in targeting the p53/E2F1 pathways and the crosstalk networks, and further propose potential therapeutic strategies for prostate cancer management.
p53 和 E2F1 信号通路在几乎所有类型的肿瘤中都存在缺陷，这表明它们的信号网络在调节肿瘤发生和治疗反应过程中起着非常重要的作用。放射治疗肿瘤学组组织样本的研究已经确定了 p53、MDM2（一种靶向 p53 进行蛋白酶体降解的 E3 泛素连接酶）和 p16（视网膜母细胞瘤的上游调节剂，因此在前列腺癌中为 E2F1）的异常表达；这些生物标志物的异常表达与放疗±雄激素剥夺治疗后的临床结果相关。尽管 p53 的促凋亡特性已有充分的文献记载，但 p53 作为活性存活信号通路介导物的新功能方面现在正逐渐显现。E2F1 是一种转录因子，具有促凋亡和促存活特性。因此，E2F1 在肿瘤发生与凋亡过程中的作用是一个有争议的问题，需要解决。此外，E2F1 在 DNA 修复中的作用也越来越受到重视。因此，抑制 E2F1 的存活和 DNA 修复能力，同时促进其凋亡功能的新方法是很有意义的。在这篇综述中，我们讨论了靶向 p53/E2F1 通路和串扰网络所涉及的挑战，并进一步提出了前列腺癌管理的潜在治疗策略。
