期刊
CANCER & METABOLISM
卷 8, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s40170-020-00234-5
关键词
ERRα p53-deficient; Mitochondrial biogenesis; Mitochondrial oxidative phosphorylation (mtOxPhos); PDX colon cancer model; Apoptosis
资金
- Hormel Foundation
- National Institutes of Health [CA187027]
Background Of the genes that control mitochondrial biogenesis and function, ERR alpha 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 ERR alpha 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 ERR alpha/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 ERR alpha and the C-terminal domain (CTD) of p53. ERR alpha binds to p53 regardless of p53 mutational status. Furthermore, we show that the ERR alpha and p53 complex cooperatively control mitochondrial biogenesis and function. Targeting ERR alpha 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 ERR alpha 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 ERR alpha/p53 transcriptional axis can be exploited as a metabolic vulnerability.
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