Martins Carla P, Brown-Swigart Lamorna, Evan Gerard I
Cancer Research Institute and Department of Cellular and Molecular Pharmacology, Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell. 2006 Dec 29;127(7):1323-34. doi: 10.1016/j.cell.2006.12.007. Epub 2006 Dec 21.
Although restoration of p53 function is an attractive tumor-specific therapeutic strategy, it remains unclear whether p53 loss is required only for transition through early bottlenecks in tumorigenesis or also for maintenance of established tumors. To explore the efficacy of p53 reinstatement as a tumor therapy, we used a reversibly switchable p53 knockin (KI) mouse model that permits modulation of p53 status from wild-type to knockout, at will. Using the well-characterized Emu-myc lymphoma model, we show that p53 is spontaneously activated when restored in established Emu-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival. Nonetheless, reimposition of p53 function potently selects for emergence of p53-resistant tumors through inactivation of p19(ARF) or p53. Our study provides important insights into the nature and timing of p53-activating signals in established tumors and how resistance to p53 evolves, which will aid in the optimization of p53-based tumor therapies.
尽管恢复p53功能是一种颇具吸引力的肿瘤特异性治疗策略，但目前尚不清楚p53缺失是否仅在肿瘤发生的早期瓶颈阶段才是必需的，还是对已形成肿瘤的维持也至关重要。为了探究恢复p53作为肿瘤治疗方法的疗效，我们使用了一种可逆性可切换的p53基因敲入（KI）小鼠模型，该模型可随意将p53状态从野生型调节为敲除型。利用特征明确的Emu-myc淋巴瘤模型，我们发现，在已形成的Emu-myc淋巴瘤体内恢复p53时，p53会自发激活，引发快速凋亡，并显著提高生存率。尽管如此，恢复p53功能会通过使p19(ARF)或p53失活，有力地选择出对p53耐药的肿瘤。我们的研究为已形成肿瘤中p53激活信号的性质和时机以及对p53的耐药性如何演变提供了重要见解，这将有助于优化基于p53的肿瘤治疗方法。
