Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Cancer Cell. 2010 Nov 16;18(5):411-22. doi: 10.1016/j.ccr.2010.10.024.
Cancer cells neutralize p53 by deletion, mutation, proteasomal degradation, or sequestration to achieve a pathologic survival advantage. Targeting the E3 ubiquitin ligase HDM2 can lead to a therapeutic surge in p53 levels. However, the efficacy of HDM2 inhibition can be compromised by overexpression of HDMX, an HDM2 homolog that binds and sequesters p53. Here, we report that a stapled p53 helix preferentially targets HDMX, blocks the formation of inhibitory p53-HDMX complexes, induces p53-dependent transcriptional upregulation, and thereby overcomes HDMX-mediated cancer resistance in vitro and in vivo. Importantly, our analysis of p53 interaction dynamics provides a blueprint for reactivating the p53 pathway in cancer by matching HDM2, HDMX, or dual inhibitors to the appropriate cellular context.
癌细胞通过缺失、突变、蛋白酶体降解或隔离来中和 p53，从而获得病理性的生存优势。靶向 E3 泛素连接酶 HDM2 可以导致 p53 水平的治疗性激增。然而，HDM2 抑制的疗效可能会因 HDMX 的过表达而受到影响，HDMX 是一种 HDM2 的同源物，它结合并隔离 p53。在这里，我们报告说，一个订书钉状的 p53 螺旋体优先靶向 HDMX，阻止形成抑制性 p53-HDMX 复合物，诱导 p53 依赖性转录上调，从而在体外和体内克服了由 HDMX 介导的癌症耐药性。重要的是，我们对 p53 相互作用动力学的分析为通过将 HDM2、HDMX 或双重抑制剂匹配到适当的细胞环境中来重新激活癌症中的 p53 途径提供了蓝图。
