Background Of the genes that control mitochondrial biogenesis and function, ERRα emerges as a druggable metabolic target to be exploited for cancer therapy. Of the genes mutated in cancer, TP53 remains the most elusive to target. A clear understanding of how mitochondrial druggable targets can be accessed to exploit the underlying mechanism(s) explaining how p53-deficient tumors promote cell survival remains elusive. Methods We performed protein-protein interaction studies to demonstrate that ERRα binds to p53. Moreover, we used gene silencing and pharmacological approaches in tandem with quantitative proteomics analysis by SWATH-MS to investigate the role of the ERRα/p53 complex in mitochondrial biogenesis and function in colon cancer. Finally, we designed in vitro and in vivo studies to investigate the possibility of targeting colon cancers that exhibit defects in p53. Results Here, we are the first to identify a direct protein-protein interaction between the ligand-binding domain (LBD) of ERRα and the C-terminal domain (CTD) of p53. ERRα binds to p53 regardless of p53 mutational status. Furthermore, we show that the ERRα and p53 complex cooperatively control mitochondrial biogenesis and function. Targeting ERRα creates mitochondrial metabolic stresses, such as production of reactive oxygen species (ROS) and mitochondrial membrane permeabilization (MMP), leading to a greater cytotoxic effect that is dependent on the presence of p53. Pharmacological inhibition of ERRα impairs the growth of p53-deficient cells and of p53 mutant patient-derived colon xenografts (PDX). Conclusions Therefore, our data suggest that by using the status of the p53 protein as a selection criterion, the ERRα/p53 transcriptional axis can be exploited as a metabolic vulnerability.

中文翻译：

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雌激素相关受体α直接与p53结合并通过调节线粒体生物发生和功能协同控制结肠癌的生长


背景 在控制线粒体生物发生和功能的基因中，ERRα 成为可用于癌症治疗的可药物代谢靶点。在癌症突变的基因中，TP53 仍然是最难以靶向的。如何清楚地了解线粒体可药物靶标以利用解释 p53 缺陷肿瘤如何促进细胞存活的潜在机制仍然难以捉摸。方法 我们进行了蛋白质-蛋白质相互作用研究，以证明 ERRα 与 p53 结合。此外，我们使用基因沉默和药理学方法，结合 SWATH-MS 定量蛋白质组学分析，研究 ERRα/p53 复合物在结肠癌线粒体生物发生和功能中的作用。最后，我们设计了体外和体内研究来研究针对 p53 缺陷的结肠癌的可能性。结果在这里，我们首次鉴定了 ERRα 的配体结合结构域 (LBD) 和 p53 的 C 末端结构域 (CTD) 之间的直接蛋白质-蛋白质相互作用。无论 p53 突变状态如何，ERRα 都会与 p53 结合。此外，我们还发现 ERRα 和 p53 复合物协同控制线粒体的生物发生和功能。靶向 ERRα 会产生线粒体代谢应激，例如活性氧 (ROS) 的产生和线粒体膜透化 (MMP)，从而导致依赖于 p53 存在的更大细胞毒性作用。 ERRα 的药理抑制会损害 p53 缺陷细胞和 p53 突变患者来源的结肠异种移植物 (PDX) 的生长。结论 因此，我们的数据表明，通过使用 p53 蛋白的状态作为选择标准，ERRα/p53 转录轴可以被利用作为代谢脆弱性。