Ceramide signaling in cancer and stem cells

Abstract

Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of 'systems interface biology': as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-1-phosphate. Lipid rafts and sphingolipid-induced protein scaffolds will be discussed as a membrane interface for lipid-controlled cell signaling. Ceramide/sphingomyelin and ceramide/ sphingosine-1-phosphate-interdependent cell-signaling pathways are significant for the regulation of cell polarity, apoptosis and/or proliferation, and as novel pharmacologic targets in cancer and stem cells. Keywordsapoptosis; cancer; cell polarity; ceramide; ES cells; lipid rafts; sphingomyelin; sphingosine-1-phosphate Ceramide & its derivatives: from metabolism to cell signalingThe structural core of ceramide is the sphingoid base sphingosine (Figure 1), a lipid that is synthesized from the amino acid serine and the activated fatty acid palmitoyl-CoA (Figure 2). Sphingosine (or sphingenine) was first isolated and characterized by the German pathologist and 'father of neurochemistry ' Johann Ludwig Wilhelm Thudichum (1829-1901 [1,2]. He coined the term sphingolipids, which is derived from 'sphingos', the genitive of Sphinx. In Greek, 'sphingo' means 'to strangle'. According to the legend, a fate of death was meant for everyone who could not solve the riddles posed by the Sphinx. Quite ironically, this is how many sphingolipid researchers may feel when faced with analyzing the function of ceramide. The riddle of ceramide, its function and how it acts as signaling lipid, is far from being solved. To ease our fears when confronted with the Sphinx in sphingolipid biochemistry, a related Greek word, 'sphingein', meaning 'to bind tight', alludes to the possibility of solving the enigma of ceramide by identifying its binding proteins.In addition to ceramide, more than a hundred different sphingolipids are known. The most comprehensive collection of sphingolipids, with respect to their characteristics and structures, can be found at [401], a Webpage supported by the National Institutes of General Medical Sciences [3,4]. Sphingolipids are essential components of cellular membranes and have been (Figure 3) . Among these, their roles as pro-or anti-apoptotic and pro-or anti-proliferative signaling lipids are the most important. Most recently, our group has found that establishment of cell polarity during embryonic development is another biological process regulated by sphingolipids [28]. To define a profile of functions for individual sphingolipids is difficult because of their rapid metabolic interconversion. To add to this predicament, several derivatives of ceramide have functions similar to ceramide itself. Hence, novel techniques are need...

tsRNA signatures in cancer

“…(19), PDGF signaling (20,21), sphingosine-1-phosphate (S1P) signaling (22), and mTOR signaling (23)(24)(25)(26). In addition, we observed an inhibition of the tumor suppressor PTEN signaling (27)(28)(29) and ceramide signaling (30). In ts-101 KO cells, two pathways related to cell transformation and cancer development are overactivated, namely, S1P signaling (22) and glutamate receptor signaling (31).…”

Reversion of Multidrug Resistance by SKI-II in SGC7901/DDP Cells and Exploration of Underlying Mechanisms

“…S1P acts as second messenger intracellularly as well as a ligand for membrane-bound G-proteincoupled receptors, and it plays an important role in regulating central cellular processes, such as cell growth, cell apoptosiss, differentiation and motility (Köberle et al, 2010;Modra., 2006;Bieberich E, 2008;Reynolds CP., 2004) by up-regulating several antiapoptotic pathways including phosphatidy-linositol-kinase or NF-κB.…”

“…Ceramide mediates a wide array of stress signals such as anticancer treatments leading to apoptosis, whereas S1P exerts prosurvival capabilities by antagonizing ceramide effects (Modrak et al, 2006). So a ceramide/S1P rheostat has been hypothesized to determine the fate of cell, such that the relative cellular concentrations of ceramide and S1P determine whether a cell proliferates or undergoes apoptosis (Andrieu-Abadie and Levade, 2002;Reynolds et al, 2004;Bieberich et al, 2008). At the same time, previous work using Dictyostelium discoideum as a model for studying drug resistance showed that mutants lacking sphingosine-1-phosphate (S1P) lyase, the enzyme that degrades S1P, had increased resistance to cisplatin, Zu-An Zhu 1 , Zheng-Qiu Zhu 2 , Hong-Xing Cai 3 , Ying Liu 4 * whereas mutants overexpressing the enzyme were more sensitive to the drug (Andrieu-Abadie and Levade, 2002).…”

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

“…These prodeath functions of ceramide are mediated through direct binding to protein targets such as the tumor suppressor phosphatase PP2A (9), kinase suppressor of Ras (10), and autophagy protein LC3B-II (7). Ceramides also play an essential role in neural stem cell differentiation, mediated via direct binding to the kinase PKC (8).…”