Exploring the link between ceramide and ionizing radiation

Abstract

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.

Crosstalk between autophagy and intracellular radiation response (Review)

“…Ceramide is localized within lipid rafts in the plasma membrane, which are specialized membrane microdomains that regulate various signaling pathways (105). Ceramide is also a central molecule of sphingolipid metabolism and involved in the regulation of autophagy at various levels (106,107). Ceramide downregulates the expression of Figure 2.…”

“…Ceramide accumulation also can induce ER stress, mTOR inhibition via TRB3 (tribbles homologue 3), which triggered lethal autophagy (111)(112)(113). Moreover, ceramide can be generated by neutral sphingomyelinase in mitochondria, which is a late event upon the cell irradiation following the early phase of ceramide accumulation at the cell plasma membrane (106). Ceramide accumulation in the mitochondria can lead to ceramide stress-induced mitochondrial fragmentation, and decrease in ATP production (114).…”

“…Radiation regulates intracellular Ca 2+ concentration through several different pathways. Firstly, radiation can induce the accumulation of ceramide, which can regulate influx of extracellular Ca 2+ at plasma membrane channel level (106). Secondly, radiation can activate PLC, the main enzyme localized at the plasma membrane and producing IP3 and consequently inducing Ca 2+ release from ER (90,118).…”

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

“…Contrary to chemotherapeutics, radiotherapy is frequently limited to tumor locations and not systemic. By using high-energy liberation of electrons, it is possible to induce cell death specifically in malignant cells (Aureli et al, 2014). This process occurs by induction of DNA damage, as radiation causes double-strand breaks in DNAs that are lethal to cells (Beckham, Cheng, et al, 2013; Carroll, Donaldson, & Obeid, 2015).…”

Role of Sphingolipids in Non-melanoma Skin Cancer

“…Numerous studies have demonstrated that ionizing radiation and DNA damaging chemotherapeutic drugs induce growth arrest and apoptosis of various cancer cells in part through generation of ceramide [ 119 ] or SPH [ 72 ]. Consequently, it is possible that these bioactive sphingolipids also mediate the therapeutic action of imiquimod or fl uorouracil in NMSC.…”