Translational aspects of sphingolipid metabolism

Zeidan, Youssef H.; Hannun, Yusuf A.

doi:10.1016/j.molmed.2007.06.002

Cited by 122 publications

(114 citation statements)

References 95 publications

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“…The balance between proapoptotic and prosurvival signaling is affected by the ratio between ceramide and sphingosine-1-phosphate or glucosylceramide. Specific types of cancers can escape from cell death by converting ceramide to sphingosine-1-phosphate or to glucosyle ceramide by SK-1 and GCS enzymes, respectively [36]. Therefore, targeting ceramide-metabolizing genes alone and in combination with anticancer agents may be an attractive treatment modality for various types of cancers.…”

Section: Discussionmentioning

confidence: 99%

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

et al. 2011

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Sphingolipids are bioeffector molecules that control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramides, the central molecule of sphingolipid metabolism, are inducer of apoptosis and inhibitors of proliferation. Sphingosine-1-phosphate (S1P) and glucosyleceramide, converted from ceramides by sphingosine kinase-1 (SK-1) and glucosyleceramide synthase (GCS) enzymes, respectively, inhibit apoptosis and develop resistance to chemotherapeutic drugs. In this study, we examined the therapeutic potentials of bioactive sphingolipids in chronic myeloid leukemia (CML) alone and in combination with dasatinib in addition to investigate the roles of ceramide-metabolizing genes in dasatinib-induced apoptosis. Cytotoxic effects of dasatinib, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by qRT-PCR. Application of ceramide analogs and inhibitors of ceramide clearance genes decreased cell proliferation and induced apoptosis. Targeting bioactive sphingolipids towards generation/accumulation of ceramides increased apoptotic effects of dasatinib, synergistically. It was shown for the first time that dasatinib induces apoptosis through downregulating expression levels of antiapoptotic SK-1 but not GCS, and upregulating expression levels of ceramide synthase (CerS) genes, especially CerS1, in K562 cells. On the other hand, dasatinib downregulates expression levels of both GCS and SK-1 and upregulate apoptotic CerS2, −5 and −6 genes in Meg-01 cells. Increasing endogenous ceramide levels and decreasing prosurvival lipids, S1P, and GC, can open the way of more effective treatment of CML.

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Section: Discussionmentioning

confidence: 99%

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

et al. 2011

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“…The biological functions of sphingolipids are diverse, encompassing structural roles through their participation in membrane lipid rafts, and signalling role via the involvement of their metabolites in signal transduction pathways. An important sphingolipid metabolite is sphingosine 1-phosphate (S1P), which mainly acts through Gprotein-coupled receptors present on mammalian cells, thereby regulating numerous cell functions, including cell proliferation, differentiation and apoptosis (Zeidan and Hannun, 2007). In the last few years, most of the studies of our group have been focused on the role played in skeletal muscle cell biology by S1P, as a modulator of intracellular Ca 2+ mobilization, phosphatidic acid synthesis and phospholipid remodelling in skeletal muscle cells (Bencini et al, 2003;Donati et al, 2005;Formigli et al, 2002;Meacci et al, 1999;Meacci et al, 2002a;Meacci et al, 2002b).…”

Section: Introductionmentioning

confidence: 99%

Regulation of transient receptor potential canonical channel 1 (TRPC1) by sphingosine 1-phosphate in C2C12 myoblasts and its relevance for a role of mechanotransduction in skeletal muscle differentiation

Formigli

Sassoli

Squecco

et al. 2009

Journal of Cell Science

106

108

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Transient receptor potential canonical (TRPC) channels provide cation and Ca2+ entry pathways, which have important regulatory roles in many physio-pathological processes, including muscle dystrophy. However, the mechanisms of activation of these channels remain poorly understood. Using siRNA, we provide the first experimental evidence that TRPC channel 1 (TRPC1), besides acting as a store-operated channel, represents an essential component of stretch-activated channels in C2C12 skeletal myoblasts, as assayed by whole-cell patch-clamp and atomic force microscopic pulling. The channel's activity and stretch-induced Ca2+ influx were modulated by sphingosine 1-phosphate (S1P), a bioactive lipid involved in satellite cell biology and tissue regeneration. We also found that TRPC1 was functionally assembled in lipid rafts, as shown by the fact that cholesterol depletion resulted in the reduction of transmembrane ion current and conductance. Association between TRPC1 and lipid rafts was increased by formation of stress fibres, which was elicited by S1P and abolished by treatment with the actin-disrupting dihydrocytochalasin B, suggesting a role for cytoskeleton in TRPC1 membrane recruitment. Moreover, TRPC1 expression was significantly upregulated during myogenesis, especially in the presence of S1P, implicating a crucial role for TRPC1 in myoblast differentiation. Collectively, these findings may offer new tools for understanding the role of TRPC1 and sphingolipid signalling in skeletal muscle regeneration and provide new therapeutic approaches for skeletal muscle disorders.

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“…Bioactive lipid molecules are receiving increasing attention due to their emerging role in the pathogenesis of human disorders including cancer, inflammation, neurological, immune and metabolic disorders (8,9). Safingol [(2S, 3S)-2-amino-1,3-octadecanediol], a bioactive lipid, is a saturated analog of sphingosine (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…Safingol [(2S, 3S)-2-amino-1,3-octadecanediol], a bioactive lipid, is a saturated analog of sphingosine (10)(11)(12). It acts as a competitive inhibitor of sphingosine kinase (SK) that prevents the formation of sphingosine-1-phosphate (S1P) (10,13), and in turn, inhibits cell proliferation, invasion and angiogenesis (8,13). Another suggested mechanism by which safingol could possibly act is by modulating protein kinase C (PKC) pathway, whereby safingol displaces phorbol dibutyrate from its lipid binding site on the regulatory domain of PKC (12,14).…”

Section: Introductionmentioning

confidence: 99%

The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells

Ling

Lin²,

Tan³

et al. 2009

Int J Oncol

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Abstract. Colon cancer represents one of the most common solid tumors in adults. Although 5-fluorouracil (5-FU) and irinotecan have been frequently administered in colon cancer patients, low response rates to these single drug therapies were reported. It is therefore imperative to search for new targeted combination therapies that are effective. In this study, we investigated the anti-cancer effect of safingol as a single agent or in combination with irinotecan using HT-29 and LS-174T colon cancer cells as our in vitro models. As a single agent, safingol was more potent than irinotecan and 5-FU, with IC 50 values of 2.5±1.1 μM and 3.4±1.0 μM achieved in HT-29 and LS-174T cells, respectively. However, protein kinase C (PKC) was not inhibited with concentrations of safingol which could induce substantial cell kill. The combination of safingol/irinotecan at 1:1 molar ratio was found to be additive in HT-29 cells (CI=0.94) and synergistic in LS-174T cells (CI=0.68), and resulted in concentration-and time-dependent down-regulation of p-PKC and p-MARCKS. The drug effect of the safingol/irinotecan combination was further modulated in the presence of a PKC stimulator (phorbol 12-myristate 13-acetate) or a PKC inhibitor (staurosporine). Furthermore, the 1:1 safingol/irinotecan combination inhibited the adhesion of colon cancer cells to the extracellular matrix 4-h post-treatment. Taken together, modulation of the PKC pathway could be a possible molecular basis for the observed synergism of the safingol/irinotecan combination, and these results demonstrate the therapeutic potential of this drug combination in colon cancer treatment.

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Translational aspects of sphingolipid metabolism

Cited by 122 publications

References 95 publications

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

Regulation of transient receptor potential canonical channel 1 (TRPC1) by sphingosine 1-phosphate in C2C12 myoblasts and its relevance for a role of mechanotransduction in skeletal muscle differentiation

The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells

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