Miller Thomas W, Soto-Pantoja David R, Schwartz Anthony L, Sipes John M, DeGraff William G, Ridnour Lisa A, Wink David A, Roberts David D
From the Laboratory of Pathology and Paradigm Shift Therapeutics, Rockville, Maryland 20852, and.
From the Laboratory of Pathology and Departments of Cancer Biology and Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
J Biol Chem. 2015 Oct 9;290(41):24858-74. doi: 10.1074/jbc.M115.665752. Epub 2015 Aug 26.
Modulating tissue responses to stress is an important therapeutic objective. Oxidative and genotoxic stresses caused by ionizing radiation are detrimental to healthy tissues but beneficial for treatment of cancer. CD47 is a signaling receptor for thrombospondin-1 and an attractive therapeutic target because blocking CD47 signaling protects normal tissues while sensitizing tumors to ionizing radiation. Here we utilized a metabolomic approach to define molecular mechanisms underlying this radioprotective activity. CD47-deficient cells and cd47-null mice exhibited global advantages in preserving metabolite levels after irradiation. Metabolic pathways required for controlling oxidative stress and mediating DNA repair were enhanced. Some cellular energetics pathways differed basally in CD47-deficient cells, and the global declines in the glycolytic and tricarboxylic acid cycle metabolites characteristic of normal cell and tissue responses to irradiation were prevented in the absence of CD47. Thus, CD47 mediates signaling from the extracellular matrix that coordinately regulates basal metabolism and cytoprotective responses to radiation injury.
调节组织对压力的反应是一个重要的治疗目标。电离辐射引起的氧化应激和基因毒性应激对健康组织有害，但对癌症治疗有益。CD47是血小板反应蛋白-1的信号受体，是一个有吸引力的治疗靶点，因为阻断CD47信号可保护正常组织，同时使肿瘤对电离辐射敏感。在这里，我们利用代谢组学方法来确定这种辐射防护活性的分子机制。CD47缺陷细胞和CD47基因敲除小鼠在辐射后维持代谢物水平方面表现出整体优势。控制氧化应激和介导DNA修复所需的代谢途径得到增强。一些细胞能量代谢途径在CD47缺陷细胞中基础上有所不同，并且在没有CD47的情况下，正常细胞和组织对辐射反应所特有的糖酵解和三羧酸循环代谢物的整体下降得到了预防。因此，CD47介导来自细胞外基质的信号，协调调节基础代谢和对辐射损伤的细胞保护反应。
