Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, Rhode Island.
Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island.
Mol Cancer Res. 2022 Apr 1;20(4):622-636. doi: 10.1158/1541-7786.MCR-21-0149.
Increased reactive oxygen species (ROS) and hyperstabilized mutant p53 are common in cancer. Hyperstabilized mutant p53 contributes to its gain of function (GOF) which confers resistance to chemotherapy and radiotherapy. Targeting mutant p53 degradation is a promising cancer therapeutic strategy. We used a small-molecule NSC59984 to explore elimination of mutant p53 in cancer cells, and identified an inducible ROS-ERK2-MDM2 axis as a vulnerability for induction of mutant p53 degradation in cancer cells. NSC59984 treatment promotes a constitutive phosphorylation of ERK2 via ROS in cancer cells. The NSC59984-sustained ERK2 activation is required for MDM2 phosphorylation at serine-166. NSC59984 enhances phosphorylated-MDM2 binding to mutant p53, which leads to mutant p53 ubiquitination and degradation. High cellular ROS increases the efficacy of NSC59984 targeting mutant p53 degradation and antitumor effects. Our data suggest that mutant p53 stabilization has a vulnerability under high ROS cellular conditions, which can be exploited by compounds to target mutant p53 protein degradation through the activation of a ROS-ERK2-MDM2 axis in cancer cells.
An inducible ROS-ERK2-MDM2 axis exposes a vulnerability in mutant p53 stabilization and can be exploited by small-molecule compounds to induce mutant p53 degradation for cancer therapy.
活性氧（ROS）增加和超稳定突变型 p53 在癌症中很常见。超稳定突变型 p53 有助于其获得功能（GOF），从而赋予对化疗和放疗的抗性。靶向突变型 p53 降解是一种有前途的癌症治疗策略。我们使用小分子 NSC59984 来探索在癌细胞中消除突变型 p53，并确定了一个可诱导的 ROS-ERK2-MDM2 轴作为诱导癌细胞中突变型 p53 降解的脆弱性。NSC59984 处理通过癌细胞中的 ROS 促进 ERK2 的组成性磷酸化。NSC59984 持续的 ERK2 激活是 MDM2 丝氨酸-166 磷酸化所必需的。NSC59984 增强了磷酸化-MDM2 与突变型 p53 的结合，导致突变型 p53 泛素化和降解。高细胞 ROS 增加了 NSC59984 靶向突变型 p53 降解和抗肿瘤作用的疗效。我们的数据表明，在高 ROS 细胞条件下，突变型 p53 的稳定具有脆弱性，这可以通过化合物来利用，通过激活癌细胞中的 ROS-ERK2-MDM2 轴来靶向突变型 p53 蛋白降解。
可诱导的 ROS-ERK2-MDM2 轴暴露了突变型 p53 稳定的脆弱性，可以通过小分子化合物来利用，诱导突变型 p53 降解用于癌症治疗。
