Targeting Tumor Suppressor p53 for Cancer Therapy: Strategies, Challenges and Opportunities
Targeting Tumor Suppressor p53 for Cancer Therapy: Strategies, Challenges and Opportunities
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DOI：
10.2174/1389450114666140106101412
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发表时间：
2014-01-01
影响因子：
3.2
通讯作者：
El-Deiry, Wafik S.
中科院分区：
文献类型：
--
作者：
Hong, Bo;van den Heuvel, A. Pieter J.;El-Deiry, Wafik S.
p53是最重要的肿瘤抑制基因之一，在人类癌症中经常发生突变。通常，p53作为转录因子起作用，其通过各种遗传毒性和细胞应激信号（例如DNA损伤、缺氧、癌基因激活和营养剥夺）稳定和激活，从而导致细胞周期停滞、凋亡、衰老和代谢适应。p53不仅在大多数癌症中变得功能缺陷，而且突变型p53也获得显性负活性和致癌特性。p53仍然是癌症治疗的有吸引力的靶点。已经开发了靶向p53的策略，包括基因治疗以恢复p53功能、抑制p53-MDM 2相互作用、将突变型p53恢复为野生型p53、靶向p53家族蛋白、消除突变型p53以及基于p53的疫苗。其中一些p53靶向疗法已经进入临床试验。我们讨论了p53的治疗潜力，特别关注在人类癌症中挽救p53失活的治疗策略。此外，我们还讨论了p53靶向治疗的挑战和未来的新机遇。
p53 is one of the most important tumor suppressor genes that is frequently mutated in human cancers. Generally, p53 functions as a transcription factor that is stabilized and activated by various genotoxic and cellular stress signals, such as DNA damage, hypoxia, oncogene activation and nutrient deprivation, consequently leading to cell cycle arrest, apoptosis, senescence and metabolic adaptation. p53 not only becomes functionally deficient in most cancers, but not infrequently mutant p53 also acquires dominant negative activity and oncogenic properties. p53 has remained an attractive target for cancer therapy. Strategies targeting p53 have been developed including gene therapy to restore p53 function, inhibition of p53-MDM2 interaction, restoration of mutant p53 to wild-type p53, targeting p53 family proteins, eliminating mutant p53, as well as p53-based vaccines. Some of these p53-targeted therapies have entered clinical trials. We discuss the therapeutic potential of p53, with particular focus on the therapeutic strategies to rescue p53 inactivation in human cancers. In addition, we discuss the challenges of p53-targeted therapy and new opportunities for the future.