Kolesnick Richard, Fuks Zvi
Laboratory of Signal Transduction, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Oncogene. 2003 Sep 1;22(37):5897-906. doi: 10.1038/sj.onc.1206702.
Ceramide is a sphingolipid that acts as a second messenger in ubiquitous, evolutionarily conserved, signaling systems. Emerging data suggest that radiation acts directly on the plasma membrane of several cell types, activating acid sphingomyelinase, which generates ceramide by enzymatic hydrolysis of sphingomyelin. Ceramide then acts as a second messenger in initiating an apoptotic response via the mitochondrial system. Radiation-induced DNA damage can also initiate ceramide generation by activation of mitochondrial ceramide synthase and de novo synthesis of ceramide. In some cells and tissues, BAX is activated downstream of ceramide, regulating commitment to the apoptotic process via release of mitochondrial cytochrome c. Genetic and pharmacologic studies in vivo showed that radiation targets the acid sphingomyelinase apoptotic system of microvascular endothelial cells in the lungs, intestines and brain, as well as in oocytes, to initiate the pathogenesis of tissue damage. Regulated ceramide metabolism may produce metabolites, such as sphingosine 1-phosphate, shown to signal antiapoptosis, thus controlling the intensity of the apoptotic response and constituting a mechanism for radiation sensitivity or resistance. An improved understanding of this signaling system may offer new opportunities for the modulation of radiation effects in the treatment of cancer.
神经酰胺是一种鞘脂，在普遍存在、进化保守的信号系统中作为第二信使发挥作用。新出现的数据表明，辐射直接作用于几种细胞类型的质膜，激活酸性鞘磷脂酶，该酶通过鞘磷脂的酶促水解产生神经酰胺。然后，神经酰胺作为第二信使，通过线粒体系统引发凋亡反应。辐射诱导的DNA损伤也可通过激活线粒体神经酰胺合酶和从头合成神经酰胺来启动神经酰胺的生成。在一些细胞和组织中，BAX在神经酰胺下游被激活，通过释放线粒体细胞色素c来调节对凋亡过程的参与。体内的遗传和药理学研究表明，辐射靶向肺、肠、脑以及卵母细胞中微血管内皮细胞的酸性鞘磷脂酶凋亡系统，从而引发组织损伤的发病机制。受调控的神经酰胺代谢可能产生代谢产物，如1-磷酸鞘氨醇，已证明其具有抗凋亡信号作用，从而控制凋亡反应的强度，并构成辐射敏感性或抗性的机制。对该信号系统的深入了解可能为癌症治疗中调节辐射效应提供新的机会。
