Aureli Massimo, Murdica Valentina, Loberto Nicoletta, Samarani Maura, Prinetti Alessandro, Bassi Rosaria, Sonnino Sandro
Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20090, Segrate, Italy.
Glycoconj J. 2014 Oct;31(6-7):449-59. doi: 10.1007/s10719-014-9541-y.
The aim of radiotherapy is to eradicate cancer cells with ionizing radiation; tumor cell death following irradiation can be induced by several signaling pathways, most of which are triggered as a consequence of DNA damage, the primary and major relevant cell response to radiation. Several lines of evidence demonstrated that ceramide, a crucial sensor and/or effector of different signalling pathways promoting cell cycle arrest, death and differentiation, is directly involved in the molecular mechanisms underlying cellular response to irradiation. Most of the studies strongly support a direct relationship between ceramide accumulation and radiation-induced cell death, mainly apoptosis; for this reason, defining the contribution of the multiple metabolic pathways leading to ceramide formation and the causes of its dysregulated metabolism represent the main goal in order to elucidate the ceramide-mediated signaling in radiotherapy. In this review, we summarize the current knowledge concerning the different routes leading to ceramide accumulation in radiation-induced cell response with particular regard to the role of the enzymes involved in both ceramide neogenesis and catabolism. Emphasis is placed on sphingolipid breakdown as mechanism of ceramide generation activated following cell irradiation; the functional relevance of this pathway, and the role of glycosphingolipid glycohydrolases as direct targets of ionizing radiation are also discussed. These new findings add a further attractive point of investigation to better define the complex interplay between sphingolipid metabolism and radiation therapy.
放射治疗的目的是利用电离辐射根除癌细胞；照射后肿瘤细胞死亡可由多种信号通路诱导，其中大多数是由DNA损伤引发的，DNA损伤是细胞对辐射的主要相关细胞反应。多项证据表明，神经酰胺作为促进细胞周期停滞、死亡和分化的不同信号通路的关键传感器和/或效应器，直接参与细胞对辐射反应的分子机制。大多数研究强烈支持神经酰胺积累与辐射诱导的细胞死亡（主要是凋亡）之间存在直接关系；因此，确定导致神经酰胺形成的多种代谢途径的作用及其代谢失调的原因，是阐明放射治疗中神经酰胺介导的信号传导的主要目标。在这篇综述中，我们总结了目前关于辐射诱导细胞反应中导致神经酰胺积累的不同途径的知识，特别关注参与神经酰胺生成和分解代谢的酶的作用。重点讨论了鞘脂分解作为细胞照射后激活的神经酰胺生成机制；还讨论了该途径的功能相关性以及糖鞘脂糖水解酶作为电离辐射直接靶点的作用。这些新发现为更好地定义鞘脂代谢与放射治疗之间的复杂相互作用增加了一个更具吸引力的研究点。
