Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells

Signorelli, Paola; Munoz-Olaya, Jose; Gagliostro, Vincenzo; Casas, Josefina; Ghidoni, Riccardo; Fabriás, Gemma

doi:10.1016/j.canlet.2009.03.020

Cited by 140 publications

(108 citation statements)

References 30 publications

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“…As shown in Fig. 3D , levels of LC3 II in cells exposed to 40 M SKI II for 24 h were higher than in control cells treated with vehicle and similar to those in cells treated with XM462 (10 M, 24 h), previously shown to induce autophagy in these cells ( 66 ).…”

Section: Ski II Inhibits Both Sk and Des1supporting

confidence: 74%

“…Several studies have reported on the induction of autophagy by treatment with drugs that increase dhCer levels, such as fenretinide, resveratrol, and ␥ -tocopherol ( 34 ). Moreover, we previously reported on the induction of autophagy with prior increase in dhCer by the Des1 inhibitor, XM462, in HGC 27 cells ( 66 ). Autophagy is also induced in the same cell model by SKI II, but not PF543 (this work).…”

Section: Discussionsupporting

confidence: 51%

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Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

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proapoptotic sphingosine (So) and ceramide (Cer). Thus, as central enzymes in modulating the Cer/S1P balance, SKs are attractive targets for cancer therapy ( 1 ). Two SKs exist in humans, SK1 and SK2. SK1 has been extensively studied and there is a large body of evidence that proves its role in promoting cell survival, proliferation, and neoplastic transformation ( 2-5 ). SK1 is also elevated in many human cancers, which appears to contribute to carcinogenesis, chemotherapeutic resistance, and poor patient outcome. SK2, however, has not been as well-characterized, and there are contradictions in the key physiological functions that have been proposed for this isoform. Despite this, many studies are now emerging that implicate SK2 in key roles in a variety of diseases, including the development of a range of solid tumors ( 6 ).The potential of SKs as therapeutic targets has boosted the development of small molecule inhibitors ( 4,(7)(8)(9)(10)(11)(12)(13)(14). A detailed characterization of their pharmacology, particularly their selectivity against human SK1 and SK2, has been published ( 15 ). The fi rst known SK inhibitors were long chain base analogs such as N , N -dimethyl-D-erythro-sphingosine (DMS) ( 16,17 ) and L-threo-dihydrosphingosine (safi ngol) ( 18-21 ). While DMS inhibits both SK1 and SK2 by (SGR 2009(SGR 1072, and the Fundació la Marató de TV3 (112130 and 112132 Abbreviations: CB5R, NADH-cytochrome b5 reductase; C16dhCer, N -hexadecanoyldihydrosphingosine ; CDH, ceramide dihexoside (lactosylceramide); Cer, ceramide; CerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphingosine; CMH, ceramide monohexoside (glucosyl and galactosylceramide); Des1, dihydroceramide desaturase; dhCDH, dihydroceramide dihexoside (lactosyldihydroceramide); dhCer, dihydroceramide; dhCerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-dihydrosphingosine; dhSM, dihydrosphingomyelin; DMS, N , N -dimethyl-D-erythro-sphingosine; FAD, fl avin adenine dinucleotide; LC3, microtubule-associated protein 1-light chain 3; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; NBD, 4-nitro-2,1,3-benzoxadiazole; PDB, Protein Data Bank; S1P, sphingosine-1-phosphate; SK, sphingosine kinase; SKI, sphingosine kinase inhibitor; So, sphingosine; TBST, TBS with 0.1% Tween 20; UPLC, ultraperformance LC . This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-22444), the Generalitat de Catalunya

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Section: Ski II Inhibits Both Sk and Des1supporting

confidence: 74%

Section: Discussionsupporting

confidence: 51%

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

Self Cite

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“…If this hypothesis is validated, dihydroceramide would serve as a unique regulator of cell fate to "switch" cytoprotective autophagy to ceramide-mediated apoptosis in response to stress. Currently, several studies have implicated dihydroceramide in the regulation of autophagy ( 153,(158)(159)(160). While the studies demonstrate the induction of autophagy in response to exogenous C2-dihydroceramide or the accumulation of endogenous dihydroceramide by resveratrol, ␥ -tocotrienol, and the dihydroceramide desaturase inhibitor XM462, the signaling pathways responsible for the induction remain undefi ned.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Young

Kester

Wang

2013

Journal of Lipid Research

294

274

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decades ago, pioneering work by Hannun et al. and Kolesnick et al. established the foundation for the bioactive nature of sphingolipids by demonstrating the inhibition of protein kinase C (PKC) by sphingosine and the stimulation of a ceramide-activated protein kinase in response to tumor necrosis factor (TNF)-␣ , respectively ( 1, 2 ). Sphingolipids have since been recognized as critical activators or inhibitors of various protein kinases and phosphatases, receptors, and ion transporters ( 3 ). Moreover, sphingolipids have been identifi ed as key regulators of a vast number of cellular processes, including cell growth, adhesion, migration, senescence, apoptosis, and most recently, autophagy ( 3, 4 ).Much of the investigation into sphingolipid signaling has focused on the disparate nature of ceramide and sphingosine-1-phosphate (S1P). Ceramide is typically associated with growth arrest and apoptosis, while S1P promotes cell proliferation and survival. The opposing nature and dynamic balance of intracellular ceramide and S1P, termed the "sphingolipid rheostat," has been proposed to determine cell fate ( 5 ). However, emerging evidence and extensive characterization of the sphingolipid metabolic network suggests that this two-dimensional model does not adequately refl ect sphingolipid signaling and function within the cell. In addition to ceramide and S1P, other sphingolipid metabolites, such as sphingosine, dihydroceramide, and gangliosides, have been implicated in the regulation of apoptosis and macroautophagy (hereafter referred to as autophagy). Although autophagy is typically considered to be a cytoprotective mechanism for the suppression of apoptosis, recent evidence indicates that autophagy can also promote cell death ( 6 ). Due to the differential regulation of apoptosis and autophagy by sphingolipid metabolites, the sphingolipid network has emerged as a novel molecular switch between the apoptotic and autophagic Abstract Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress. Although the two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators. The crosstalk between apoptosis and autophagy is complex, as autophagy can function to promote cell survival or cell death under various cellular conditions. The molecular mechanisms of crosstalk are beginning to be elucidated and have critical implications for the treatment of various diseases, such as cancer. Sphingolipids are a class of bioactive lipids that mediate many key cellular processes, including apoptosis and autophagy. By targeting several of the shared regulators, sphingolipid metabolites differentially regulate the induction of apoptosis and autophagy. Importantly, individual sphingolipid species appear to "switch" autophagy toward cell survival (e.g., sphingosine-1-phosphate) or cell death (e.g., ceramide, gangliosides). This review assesses the current understanding of sphingolipid-induced apoptosis and autophagy to addr...

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“…Loss of dhCer was correlated with rapid cell growth and increased apoptosis interestingly, and this phenotype was rescued with the activation of dhCer synthesis in some neurodegerative disorders [96]. Autophagy, self-destruction of the cellular components, is another process in which dhCer is thought to have regulatory roles [97,98]. In some studies it was documented that not the increased intracellular dhCer level; but the conversion of dhCer into other sphingolipids per se is responsible for some of the listed phenotypes above [99].…”

Section: Dihydrosphingosinementioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells

Cited by 140 publications

References 30 publications

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

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