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Antonio Gómez-muñoz - One of the best experts on this subject based on the ideXlab platform.
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Novel signaling aspects of Ceramide 1-Phosphate
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2020Co-Authors: Natalia Presa, Ana Gomez-larrauri, Miguel Trueba, Asier Dominguez-herrera, Antonio Gómez-muñozAbstract:The bioactive sphingolipid Ceramide 1-Phosphate (C1P) regulates key physiologic cell functions and is implicated in a number of metabolic alterations and pathological processes. Initial studies using different types of fibroblasts and monocytes/macrophages revealed that C1P was mitogenic and that it promoted cell survival through inhibition of apoptosis. Subsequent studies implicated C1P in inflammatory responses with a specific role as pro-inflammatory agent. Specifically, C1P potently stimulated cytosolic phospholipase A2 (cPLA2) resulting in elevation of arachidonic acid and pro-inflammatory eicosanoid levels. However, increasing experimental evidence suggests that C1P can also exert anti-inflammatory actions in some cell types and tissues. Specifically, it has been demonstrated that C1P inhibits the release of pro-inflammatory cytokines and blocks activation of the pro-inflammatory transcription factor NF-κB in some cell types. Moreover, C1P was shown to increase the release of anti-inflammatory interleukin-10 in macrophages, and to overcome airway inflammation and reduce lung emphysema in vivo. Noteworthy, C1P stimulated cell migration, an action that is associated with diverse physiological cell functions, as well as with inflammatory responses and tumor dissemination. More recently, Ceramide kinase (CerK), the enzyme that produces C1P in mammalian cells, has been shown to be upregulated during differentiation of pre-adipocytes into mature adipocytes, and that exogenous C1P, acting through a putative Gi protein-coupled receptor, negatively regulates adipogenesis. Although the latter actions seem to be contradictory, it is plausible that exogenous C1P may balance the adipogenic effects of intracellularly generated (CerK-derived) C1P in adipose tissue. The present review highlights novel signaling aspects of C1P and its impact in the regulation of cell growth and survival, inflammation and tumor dissemination.
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The Role of Ceramide 1-Phosphate in Tumor Cell Survival and Dissemination.
Advances in cancer research, 2018Co-Authors: Antonio Gómez-muñozAbstract:Ceramide 1-Phosphate (C1P) is a pleiotropic bioactive sphingolipid metabolite capable of regulating key physiologic cell functions and promoting pathologic processes. Concerning pathology, C1P or Ceramide kinase (CerK), the enzyme responsible for its biosynthesis in mammalian cells, has been implicated in cancer cell growth, survival, and dissemination and is involved in inflammatory responses associated with different types of cancer cells. The mechanisms or signaling pathways mediating these C1P actions have only been partially described. This chapter reviews recent progress in identifying signal transduction pathways involved in the promotion of cancer cell growth, survival, and dissemination by CerK and C1P.
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Lysophosphatidic Acid Signaling Axis Mediates Ceramide 1-Phosphate-Induced Proliferation of C2C12 Myoblasts.
International journal of molecular sciences, 2018Co-Authors: Caterina Bernacchioni, Antonio Gómez-muñoz, Alberto Ouro, Chiara Donati, Francesca Cencetti, Marina Bruno, Paola BruniAbstract:Sphingolipids are not only crucial for membrane architecture but act as critical regulators of cell functions. The bioactive sphingolipid Ceramide 1-Phosphate (C1P), generated by the action of Ceramide kinase, has been reported to stimulate cell proliferation, cell migration and to regulate inflammatory responses via activation of different signaling pathways. We have previously shown that skeletal muscle is a tissue target for C1P since the phosphosphingolipid plays a positive role in myoblast proliferation implying a role in muscle regeneration. Skeletal muscle displays strong capacity of regeneration thanks to the presence of quiescent adult stem cells called satellite cells that upon trauma enter into the cell cycle and start proliferating. However, at present, the exact molecular mechanism by which C1P triggers its mitogenic effect in myoblasts is lacking. Here, we report for the first time that C1P stimulates C2C12 myoblast proliferation via lysophosphatidic acid (LPA) signaling axis. Indeed, C1P subsequently to phospholipase A2 activation leads to LPA1 and LPA3 engagement, which in turn drive Akt (protein kinase B) and ERK1/2 (extracellular signal-regulated kinases 1/2) activation, thus stimulating DNA synthesis. The present findings shed new light on the key role of bioactive sphingolipids in skeletal muscle and provide further support to the notion that these pleiotropic molecules might be useful therapeutic targets for skeletal muscle regeneration.
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Vascular endothelial growth factor mediates Ceramide 1-Phosphate-stimulated macrophage proliferation.
Experimental cell research, 2017Co-Authors: Alberto Ouro, Ana Gomez-larrauri, Lide Arana, Maziar Riazy, Peng Zhang, Urs P. Steinbrecher, Vincent Duronio, Antonio Gómez-muñozAbstract:Abstract The bioactive sphingolipid Ceramide 1-Phosphate (C1P) regulates cell division in a variety of cell types including macrophages. However, the mechanisms involved in this action are not completely understood. In the present work we show that C1P stimulates the release of vascular endothelial growth factor (VEGF) in RAW264.7 macrophages, and that this growth factor is essential for stimulation of cell proliferation by C1P. The stimulation of VEGF release was dependent upon activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB-1 also known as Akt-1), and mitogen-activated protein kinase-kinase (MEK)/extracellularly regulated kinase-2 (ERK-2) pathways, as inhibition of these kinases with selective pharmacological inhibitors or with specific gene silencing siRNA, abrogated VEGF release. A key observation was that sequestration of VEGF with a neutralizing antibody, or treatment with VEGF siRNA abolished C1P-stimulated macrophage growth. Also, inhibition of the pathways involved in C1P-stimulated VEGF release inhibited the stimulation of macrophage growth by C1P. Moreover, blockade of VEGF receptor-2 (VEGFR-2), which is the primary receptor for VEGF, with the pharmacological inhibitor DMH4, or with specific VEGFR-2 siRNA, substantially inhibited C1P-stimulated cell growth. It can be concluded that stimulation of VEGF release is a key factor in the promotion of macrophage proliferation by C1P.
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Implication of matrix metalloproteinases 2 and 9 in Ceramide 1-Phosphate-stimulated macrophage migration
Cellular signalling, 2016Co-Authors: Marta Ordoñez, Natalia Presa, Io-guané Rivera, Antonio Gómez-muñozAbstract:Cell migration is a complex biological function involved in both physiologic and pathologic processes. Although this is a subject of intense investigation, the mechanisms by which cell migration is regulated are not completely understood. In this study we show that the bioactive sphingolipid Ceramide 1-Phosphate (C1P), which is involved in inflammatory responses, causes upregulation of metalloproteinases (MMP) -2 and -9 in J774A.1 macrophages. This effect was shown to be dependent on stimulation of phosphatidylinositol 3-kinase (PI3K) and extracellularly regulated kinases 1-2 (ERK1-2) as demonstrated by treating the cells with specific siRNA to knockdown the p85 regulatory subunit of PI3K, or ERK1-2. Inhibition of MMP-2 or MMP-9 pharmacologically or with specific siRNA to silence the genes encoding these MMPs abrogated C1P-stimulated macrophage migration. Also, C1P induced actin polymerization and potently increased phosphorylation of the focal adhesion protein paxillin, which are essential factors in the regulation of cell migration. As expected, blockade of paxillin activation with specific siRNA significantly reduced actin polymerization. In addition, inhibition of actin polymerization with cytochalasin D completely blocked C1P-induced MMP-2 and -9 expression as well as C1P-stimulated macrophage migration. It was also observed that pertussis toxin (Ptx) inhibited Akt, ERK1-2, and paxillin phosphorylation, and completely blocked cell migration. The latter findings support the notion that C1P-stimulated macrophage migration is a receptor mediated effect, and point to MMP-2 and -9 as possible therapeutic targets to control inflammation.
Charles E Chalfant - One of the best experts on this subject based on the ideXlab platform.
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The Role of Ceramide 1-Phosphate in Inflammation, Cellular Proliferation, and Wound Healing.
Advances in experimental medicine and biology, 2019Co-Authors: Melissa L Berwick, Brittany A Dudley, Kenneth D. Maus, Charles E ChalfantAbstract:The phospho-sphingolipid, Ceramide 1-Phosphate (C1P), has long been implicated as a dynamic bioactive agent. Over two decades of research has begun to characterize various regulatory roles for C1P from mammalian inflammatory response and wound healing to cellular proliferation and survival. As a metabolite of the intricately balanced "sphingolipid rheostat", C1P stands as a crucial physiological regulator of both upstream and downstream mechanisms. This chapter serves as an overview of established and implicated roles for C1P in cellular processes vital to diseases and mammalian physiology. Additionally, we discuss potential clinical roles for C1P in cancer treatment, wound therapy, and pre-disease diagnosis. While many questions remain regarding C1P metabolism and the extent of signaling factors targeted by this bioactive lipid, new technologies and methodologies show great promise to discern key targets, signaling pathways, and physiologies regulated by C1P.
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non vesicular trafficking by a Ceramide 1 Phosphate transfer protein regulates eicosanoids
Nature, 2013Co-Authors: Dhirendra K. Simanshu, Dayanjan S. Wijesinghe, Charles E Chalfant, Julian G. Molotkovsky, Xiuhong Zhai, Lucy Malinina, Shrawan K. Mishra, Edward H. Hinchcliffe, Ravi Kanth KamlekarAbstract:Phosphorylated sphingolipids Ceramide-1-Phosphate (C1P) and sphingosine-1-Phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation. C1P produced by Ceramide kinase is an activator of group IVA cytosolic phospholipase A2α (cPLA2α), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma or airway hyper-responsiveness, cancer, atherosclerosis and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. Vesicular trafficking is likely but non-vesicular mechanisms for C1P sensing, transfer and presentation remain unexplored. Moreover, the molecular basis for selective recognition and binding among signalling lipids with Phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, Phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, α-helically-dominated 'sandwich' topology identifies CPTP as the prototype for a new glycolipid transfer protein fold subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi network, nucleus and plasma membrane. RNA interference-induced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2α release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.
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The Molecular Basis of Ceramide-1-Phosphate Recognition by C2 Domains
Journal of lipid research, 2012Co-Authors: Katherine E. Ward, Charles E Chalfant, Nitin Bhardwaj, Mohsin Vora, Robert V. StahelinAbstract:Group IVA cytosolic phospholipase A2 (cPLA2α), which harbors an N-terminal lipid binding C2 domain and a C-terminal lipase domain, produces arachidonic acid from the sn-2 position of zwitterionic lipids such as phosphatidylcholine. The C2 domain has been shown to bind zwitterionic lipids, but more recently, the anionic phosphomonoester sphingolipid metabolite Ceramide-1-Phosphate (C1P) has emerged as a potent bioactive lipid with high affinity for a cationic patch in the C2 domain β-groove. To systematically analyze the role that C1P plays in promoting the binding of cPLA2α-C2 to biological membranes, we employed biophysical measurements and cellular translocation studies along with mutagenesis. Biophysical and cellular translocation studies demonstrate that C1P specificity is mediated by Arg59, Arg61, and His62 (an RxRH sequence) in the C2 domain. Computational studies using molecular dynamics simulations confirm the origin of C1P specificity, which results in a spatial shift of the C2 domain upon membrane docking to coordinate the small C1P headgroup. Additionally, the hydroxyl group on the sphingosine backbone plays an important role in the interaction with the C2 domain, further demonstrating the selectivity of the C2 domain for C1P over phosphatidic acid. Taken together, this is the first study demonstrating the molecular origin of C1P recognition.
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Ceramide 1 Phosphate is required for the translocation of group iva cytosolic phospholipase a2 and prostaglandin synthesis
Journal of Biological Chemistry, 2009Co-Authors: Nadia F. Lamour, Dayanjan S. Wijesinghe, Preeti Subramanian, Robert V. Stahelin, Joseph V Bonventre, Charles E ChalfantAbstract:Abstract Little is known about the regulation of eicosanoid synthesis proximal to the activation of cytosolic phospholipase A2α (cPLA2α), the initial rate-limiting step. The current view is that cPLA2α associates with intracellular/phosphatidylcholine-rich membranes strictly via hydrophobic interactions in response to an increase of intracellular calcium. In opposition to this accepted mechanism of two decades, Ceramide 1-Phosphate (C1P) has been shown to increase the membrane association of cPLA2α in vitro via a novel site in the cationic β-groove of the C2 domain (Stahelin, R. V., Subramanian, P., Vora, M., Cho, W., and Chalfant, C. E. (2007) J. Biol. Chem. 282, 20467–204741). In this study we demonstrate that C1P is a proximal and required bioactive lipid for the translocation of cPLA2α to intracellular membranes in response to inflammatory agonists (e.g. calcium ionophore and ATP). Last, the absolute requirement of the C1P/cPLA2α interaction was demonstrated for the production of eicosanoids using murine embryonic fibroblasts (cPLA2α−/−) coupled to “rescue” studies. Therefore, this study provides a paradigm shift in how cPLA2α is activated during inflammation.
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Ceramide 1 Phosphate is required for the translocation of group iva cytosolic phospholipase a2 and prostaglandin synthesis
Journal of Biological Chemistry, 2009Co-Authors: Nadia F. Lamour, Dayanjan S. Wijesinghe, Preeti Subramanian, Robert V. Stahelin, Joseph V Bonventre, Charles E ChalfantAbstract:Little is known about the regulation of eicosanoid synthesis proximal to the activation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), the initial rate-limiting step. The current view is that cPLA(2)alpha associates with intracellular/phosphatidylcholine-rich membranes strictly via hydrophobic interactions in response to an increase of intracellular calcium. In opposition to this accepted mechanism of two decades, Ceramide 1-Phosphate (C1P) has been shown to increase the membrane association of cPLA(2)alpha in vitro via a novel site in the cationic beta-groove of the C2 domain (Stahelin, R. V., Subramanian, P., Vora, M., Cho, W., and Chalfant, C. E. (2007) J. Biol. Chem. 282, 20467-204741). In this study we demonstrate that C1P is a proximal and required bioactive lipid for the translocation of cPLA(2)alpha to intracellular membranes in response to inflammatory agonists (e.g. calcium ionophore and ATP). Last, the absolute requirement of the C1P/cPLA(2)alpha interaction was demonstrated for the production of eicosanoids using murine embryonic fibroblasts (cPLA(2)alpha(-/-)) coupled to "rescue" studies. Therefore, this study provides a paradigm shift in how cPLA(2)alpha is activated during inflammation.
Patricia Gangoiti - One of the best experts on this subject based on the ideXlab platform.
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Ceramide 1-Phosphate regulates cell migration and invasion of human pancreatic cancer cells.
Biochemical pharmacology, 2015Co-Authors: Io-guané Rivera, Natalia Presa, Ana Gomez-larrauri, Marta Ordoñez, Miguel Trueba, Patricia Gangoiti, Todd E. Fox, Mark Kester, Antonio Gómez-muñozAbstract:Pancreatic cancer is an aggressive and devastating disease characterized by invasiveness, rapid progression and profound resistance to treatment. Despite years of intense investigation, the prognosis of this type of cancer is poor and there is no efficacious treatment to overcome the disease. Using human PANC-1 and MIA PaCa-2 cells, we demonstrate that the bioactive sphingolipid Ceramide 1-Phosphate (C1P) increases pancreatic cancer cell migration and invasion. Treatment of these cells with selective inhibitors of phosphatidylinositol 3-kinase (PI3K), Akt1, or mammalian target of rapamycin 1 (mTOR1), or with specific siRNAs to silence the genes encoding these kinases, resulted in potent inhibition of C1P-induced cell migration and invasion. Likewise, the extracellularly regulated kinases 1 and 2 (ERK1-2), and the small GTPase RhoA, which regulates cytoskeleton reorganization, were also found to be implicated in C1P-stimulated ROCK1-dependent cancer cell migration and invasion. In addition, pre-treatment of the cancer cells with pertussis toxin abrogated C1P-induced cell migration, suggesting the intervention of a Gi protein-coupled receptor in this process. Pancreatic cancer cells engineered to overexpress Ceramide kinase (CerK), the enzyme responsible for C1P biosynthesis in mammalian cells, showed enhanced spontaneous cell migration that was potently blocked by treatment with the selective CerK inhibitor NVP-231, or by treatment with specific CerK siRNA. Moreover, overexpression of CerK with concomitant elevations in C1P enhanced migration of pancreatic cancer cells. Collectively, these data demonstrate that C1P is a key regulator of pancreatic cancer cell motility, and suggest that targeting CerK expression/activity and C1P may be relevant factors for controlling pancreatic cancer cell dissemination.
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Caged Ceramide 1-Phosphate (C1P) analogs: Novel tools for studying C1P biology.
Chemistry and physics of lipids, 2015Co-Authors: Antonio Gómez-muñoz, Natalia Presa, Ana Gomez-larrauri, Io-guané Rivera, Patricia Gangoiti, Marta OrdoñezAbstract:Ceramide 1-Phosphate (C1P) is a bioactive sphingolipid metabolite that is produced in cells by the action of Ceramide kinase (CerK) acting upon Ceramide, and is also found in the circulation. C1P was first demonstrated to be mitogenic and antiapoptotic in different cell types, and was later shown to induce cell migration. Understanding the precise mechanisms by which C1P exerts its biological effects has been possible using specific photosensitive caged C1P analogues synthesized by Robert Bittman's group. These compounds are cell permeable, bypass cell plasma membrane receptors, and can be released into the cytosol upon light irradiation, thereby allowing precise determination of the intracellular mechanisms of actions of C1P. Two derivatives of N-palmitoyl-Ceramide 1-Phosphate have been used in most studies. In one C1P derivative the cage was 7-(N,N-diethylamino)coumarin (DECM-C1P) while in the other it was a 4-bromo-5-hydroxy-2-nitrobenzhydryl moiety (BHNB-C1P). The uncaging process released C1P in the cytosol, and this was accompanied by stimulation of cell proliferation, inhibition of apoptosis, and production of low levels of reactive oxygen species. However, intracellular accumulation of C1P did not affect chemotaxis. The caged C1P analogues allowed distinction between the extracellular events evoked by C1P, as for example through interaction with a putative cell-surface receptor, from its intracellular effects.
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Phosphatidic acid inhibits Ceramide 1-Phosphate-stimulated macrophage migration
Biochemical pharmacology, 2014Co-Authors: Alberto Ouro, Natalia Presa, Ana Gomez-larrauri, Io-guané Rivera, Marta Ordoñez, Miguel Trueba, Patricia Gangoiti, Lide Arana, Jorge Simón, Robert BittmanAbstract:Ceramide 1-Phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis.
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Ceramide 1-Phosphate induces macrophage chemoattractant protein-1 release: involvement in Ceramide 1-Phosphate-stimulated cell migration
American journal of physiology. Endocrinology and metabolism, 2013Co-Authors: Lide Arana, Io-guané Rivera, Marta Ordoñez, Miguel Trueba, Patricia Gangoiti, Alberto Ouro, Antonio Gómez-muñozAbstract:The bioactive sphingolipid Ceramide 1-Phosphate (C1P) is implicated in inflammatory responses and was recently shown to promote cell migration. However, the mechanisms involved in these actions are...
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New insights on the role of Ceramide 1-Phosphate in inflammation
Biochimica et biophysica acta, 2013Co-Authors: Antonio Gómez-muñoz, Io-guané Rivera, Marta Ordoñez, Patricia Gangoiti, Alberto Ouro, Lide Arana, Miguel TruebaAbstract:Abstract Inflammation is a complex biological process involving a variety of locally produced molecules, as well as different types of white blood cells. Some of the so-called inflammatory mediators include cytokines, chemokines, interleukins, prostaglandins, or bioactive lipids, all of which provide protection from infection and foreign substances, such as bacteria, yeast, viruses or some chemicals. Under some circumstances, however, the organism inappropriately activates the immune system triggering an inflammatory response in the absence of foreign insults thereby leading to the establishment of autoimmune diseases. Therefore, inflammation must be tightly regulated in order to ensure sufficient protection to the organism in the absence of unwanted, and at times dangerous, side effects. Increasing experimental evidence implicates sphingolipids as major inducers of inflammatory responses and regulators of immune cell functions. In particular, Ceramides and sphingosine 1-Phosphate have been extensively implicated in inflammation, and Ceramide 1-Phosphate has also been shown to participate in these processes. The present review highlights novel aspects on the regulation of inflammation by sphingolipids, with special emphasis to the role played by Ceramide 1-phoshate and Ceramide kinase, the enzyme responsible for its biosynthesis, in inflammatory responses.
Marta Ordoñez - One of the best experts on this subject based on the ideXlab platform.
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Implication of matrix metalloproteinases 2 and 9 in Ceramide 1-Phosphate-stimulated macrophage migration
Cellular signalling, 2016Co-Authors: Marta Ordoñez, Natalia Presa, Io-guané Rivera, Antonio Gómez-muñozAbstract:Cell migration is a complex biological function involved in both physiologic and pathologic processes. Although this is a subject of intense investigation, the mechanisms by which cell migration is regulated are not completely understood. In this study we show that the bioactive sphingolipid Ceramide 1-Phosphate (C1P), which is involved in inflammatory responses, causes upregulation of metalloproteinases (MMP) -2 and -9 in J774A.1 macrophages. This effect was shown to be dependent on stimulation of phosphatidylinositol 3-kinase (PI3K) and extracellularly regulated kinases 1-2 (ERK1-2) as demonstrated by treating the cells with specific siRNA to knockdown the p85 regulatory subunit of PI3K, or ERK1-2. Inhibition of MMP-2 or MMP-9 pharmacologically or with specific siRNA to silence the genes encoding these MMPs abrogated C1P-stimulated macrophage migration. Also, C1P induced actin polymerization and potently increased phosphorylation of the focal adhesion protein paxillin, which are essential factors in the regulation of cell migration. As expected, blockade of paxillin activation with specific siRNA significantly reduced actin polymerization. In addition, inhibition of actin polymerization with cytochalasin D completely blocked C1P-induced MMP-2 and -9 expression as well as C1P-stimulated macrophage migration. It was also observed that pertussis toxin (Ptx) inhibited Akt, ERK1-2, and paxillin phosphorylation, and completely blocked cell migration. The latter findings support the notion that C1P-stimulated macrophage migration is a receptor mediated effect, and point to MMP-2 and -9 as possible therapeutic targets to control inflammation.
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Regulation of cell migration and inflammation by Ceramide 1-Phosphate.
Biochimica et biophysica acta, 2016Co-Authors: Natalia Presa, Ana Gomez-larrauri, Io-guané Rivera, Marta Ordoñez, Miguel Trueba, Antonio Gómez-muñozAbstract:Abstract Ceramide 1-Phosphate (C1P) is a bioactive sphingolipid metabolite first shown to regulate cell growth and death. Subsequent studies revealed that C1P was a potent stimulator of cytosolic phospholipase A2 (cPLA2) with ensuing release of arachidonic acid and prostaglandin biosynthesis. The latter findings placed C1P on the list of pro-inflammatory metabolites. More recently, C1P was found to potently stimulate cell migration, an action that is associated to diverse physiological effects, as well as to inflammatory responses and tumor dissemination. The implication of C1P in inflammation has gained further interest in the last few years due to the discovery that it can exert anti-inflammatory actions in some cell types and tissues. In particular, C1P has been demonstrated to inhibit pro-inflammatory cytokine release and blockade of the pro-inflammatory transcription factor NF-κB in some cell types, as well as to reduce airway inflammation and lung emphysema. The present review is focused on novel aspects of C1P regulation of cell migration and the impact of C1P as novel anti-inflammatory agent. Gloss Ceramide 1-Phosphate (C1P) is a phosphosphingolipid with potent biological activities. It promotes cell growth and survival, and is a key regulator of cell migration. Both C1P and the enzyme that catalyzes its biosynthesis, Ceramide kinase, are implicated in inflammatory responses. Although C1P has pro-inflammatory properties, it reduces pulmonary emphysema and exerts anti-inflammatory actions in the lung. Synthetic C1P analogs may be promising tools to treat lung inflammation.
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Ceramide 1-Phosphate regulates cell migration and invasion of human pancreatic cancer cells.
Biochemical pharmacology, 2015Co-Authors: Io-guané Rivera, Natalia Presa, Ana Gomez-larrauri, Marta Ordoñez, Miguel Trueba, Patricia Gangoiti, Todd E. Fox, Mark Kester, Antonio Gómez-muñozAbstract:Pancreatic cancer is an aggressive and devastating disease characterized by invasiveness, rapid progression and profound resistance to treatment. Despite years of intense investigation, the prognosis of this type of cancer is poor and there is no efficacious treatment to overcome the disease. Using human PANC-1 and MIA PaCa-2 cells, we demonstrate that the bioactive sphingolipid Ceramide 1-Phosphate (C1P) increases pancreatic cancer cell migration and invasion. Treatment of these cells with selective inhibitors of phosphatidylinositol 3-kinase (PI3K), Akt1, or mammalian target of rapamycin 1 (mTOR1), or with specific siRNAs to silence the genes encoding these kinases, resulted in potent inhibition of C1P-induced cell migration and invasion. Likewise, the extracellularly regulated kinases 1 and 2 (ERK1-2), and the small GTPase RhoA, which regulates cytoskeleton reorganization, were also found to be implicated in C1P-stimulated ROCK1-dependent cancer cell migration and invasion. In addition, pre-treatment of the cancer cells with pertussis toxin abrogated C1P-induced cell migration, suggesting the intervention of a Gi protein-coupled receptor in this process. Pancreatic cancer cells engineered to overexpress Ceramide kinase (CerK), the enzyme responsible for C1P biosynthesis in mammalian cells, showed enhanced spontaneous cell migration that was potently blocked by treatment with the selective CerK inhibitor NVP-231, or by treatment with specific CerK siRNA. Moreover, overexpression of CerK with concomitant elevations in C1P enhanced migration of pancreatic cancer cells. Collectively, these data demonstrate that C1P is a key regulator of pancreatic cancer cell motility, and suggest that targeting CerK expression/activity and C1P may be relevant factors for controlling pancreatic cancer cell dissemination.
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Control of inflammatory responses by Ceramide, sphingosine 1-Phosphate and Ceramide 1-Phosphate.
Progress in Lipid Research, 2015Co-Authors: Antonio Gómez-muñoz, Natalia Presa, Ana Gomez-larrauri, Io-guané Rivera, Miguel Trueba, Marta OrdoñezAbstract:Inflammation is a network of complex processes involving a variety of metabolic and signaling pathways aiming at healing and repairing damage tissue, or fighting infection. However, inflammation can be detrimental when it becomes out of control. Inflammatory mediators involve cytokines, bioactive lipids and lipid-derived metabolites. In particular, the simple sphingolipids Ceramides, sphingosine 1-Phosphate, and Ceramide 1-Phosphate have been widely implicated in inflammation. However, although Ceramide 1-Phosphate was first described as pro-inflammatory, recent studies show that it has anti-inflammatory properties when produced in specific cell types or tissues. The biological functions of Ceramides and sphingosine 1-Phosphate have been extensively studied. These sphingolipids have opposing effects with Ceramides being potent inducers of cell cycle arrest and apoptosis, and sphingosine 1-Phosphate promoting cell growth and survival. However, the biological actions of Ceramide 1-Phosphate have only been partially described. Ceramide 1-Phosphate is mitogenic and anti-apoptotic, and more recently, it has been demonstrated to be key regulator of cell migration. Both sphingosine 1-Phosphate and Ceramide 1-Phosphate are also implicated in tumor growth and dissemination. The present review highlights new aspects on the control of inflammation and cell migration by simple sphingolipids, with special emphasis to the role played by Ceramide 1-Phosphate in controlling these actions.
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Caged Ceramide 1-Phosphate (C1P) analogs: Novel tools for studying C1P biology.
Chemistry and physics of lipids, 2015Co-Authors: Antonio Gómez-muñoz, Natalia Presa, Ana Gomez-larrauri, Io-guané Rivera, Patricia Gangoiti, Marta OrdoñezAbstract:Ceramide 1-Phosphate (C1P) is a bioactive sphingolipid metabolite that is produced in cells by the action of Ceramide kinase (CerK) acting upon Ceramide, and is also found in the circulation. C1P was first demonstrated to be mitogenic and antiapoptotic in different cell types, and was later shown to induce cell migration. Understanding the precise mechanisms by which C1P exerts its biological effects has been possible using specific photosensitive caged C1P analogues synthesized by Robert Bittman's group. These compounds are cell permeable, bypass cell plasma membrane receptors, and can be released into the cytosol upon light irradiation, thereby allowing precise determination of the intracellular mechanisms of actions of C1P. Two derivatives of N-palmitoyl-Ceramide 1-Phosphate have been used in most studies. In one C1P derivative the cage was 7-(N,N-diethylamino)coumarin (DECM-C1P) while in the other it was a 4-bromo-5-hydroxy-2-nitrobenzhydryl moiety (BHNB-C1P). The uncaging process released C1P in the cytosol, and this was accompanied by stimulation of cell proliferation, inhibition of apoptosis, and production of low levels of reactive oxygen species. However, intracellular accumulation of C1P did not affect chemotaxis. The caged C1P analogues allowed distinction between the extracellular events evoked by C1P, as for example through interaction with a putative cell-surface receptor, from its intracellular effects.
Alberto Ouro - One of the best experts on this subject based on the ideXlab platform.
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Lysophosphatidic Acid Signaling Axis Mediates Ceramide 1-Phosphate-Induced Proliferation of C2C12 Myoblasts.
International journal of molecular sciences, 2018Co-Authors: Caterina Bernacchioni, Antonio Gómez-muñoz, Alberto Ouro, Chiara Donati, Francesca Cencetti, Marina Bruno, Paola BruniAbstract:Sphingolipids are not only crucial for membrane architecture but act as critical regulators of cell functions. The bioactive sphingolipid Ceramide 1-Phosphate (C1P), generated by the action of Ceramide kinase, has been reported to stimulate cell proliferation, cell migration and to regulate inflammatory responses via activation of different signaling pathways. We have previously shown that skeletal muscle is a tissue target for C1P since the phosphosphingolipid plays a positive role in myoblast proliferation implying a role in muscle regeneration. Skeletal muscle displays strong capacity of regeneration thanks to the presence of quiescent adult stem cells called satellite cells that upon trauma enter into the cell cycle and start proliferating. However, at present, the exact molecular mechanism by which C1P triggers its mitogenic effect in myoblasts is lacking. Here, we report for the first time that C1P stimulates C2C12 myoblast proliferation via lysophosphatidic acid (LPA) signaling axis. Indeed, C1P subsequently to phospholipase A2 activation leads to LPA1 and LPA3 engagement, which in turn drive Akt (protein kinase B) and ERK1/2 (extracellular signal-regulated kinases 1/2) activation, thus stimulating DNA synthesis. The present findings shed new light on the key role of bioactive sphingolipids in skeletal muscle and provide further support to the notion that these pleiotropic molecules might be useful therapeutic targets for skeletal muscle regeneration.
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Vascular endothelial growth factor mediates Ceramide 1-Phosphate-stimulated macrophage proliferation.
Experimental cell research, 2017Co-Authors: Alberto Ouro, Ana Gomez-larrauri, Lide Arana, Maziar Riazy, Peng Zhang, Urs P. Steinbrecher, Vincent Duronio, Antonio Gómez-muñozAbstract:Abstract The bioactive sphingolipid Ceramide 1-Phosphate (C1P) regulates cell division in a variety of cell types including macrophages. However, the mechanisms involved in this action are not completely understood. In the present work we show that C1P stimulates the release of vascular endothelial growth factor (VEGF) in RAW264.7 macrophages, and that this growth factor is essential for stimulation of cell proliferation by C1P. The stimulation of VEGF release was dependent upon activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB-1 also known as Akt-1), and mitogen-activated protein kinase-kinase (MEK)/extracellularly regulated kinase-2 (ERK-2) pathways, as inhibition of these kinases with selective pharmacological inhibitors or with specific gene silencing siRNA, abrogated VEGF release. A key observation was that sequestration of VEGF with a neutralizing antibody, or treatment with VEGF siRNA abolished C1P-stimulated macrophage growth. Also, inhibition of the pathways involved in C1P-stimulated VEGF release inhibited the stimulation of macrophage growth by C1P. Moreover, blockade of VEGF receptor-2 (VEGFR-2), which is the primary receptor for VEGF, with the pharmacological inhibitor DMH4, or with specific VEGFR-2 siRNA, substantially inhibited C1P-stimulated cell growth. It can be concluded that stimulation of VEGF release is a key factor in the promotion of macrophage proliferation by C1P.
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Phosphatidic acid inhibits Ceramide 1-Phosphate-stimulated macrophage migration
Biochemical pharmacology, 2014Co-Authors: Alberto Ouro, Natalia Presa, Ana Gomez-larrauri, Io-guané Rivera, Marta Ordoñez, Miguel Trueba, Patricia Gangoiti, Lide Arana, Jorge Simón, Robert BittmanAbstract:Ceramide 1-Phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis.
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Ceramide 1-Phosphate induces macrophage chemoattractant protein-1 release: involvement in Ceramide 1-Phosphate-stimulated cell migration
American journal of physiology. Endocrinology and metabolism, 2013Co-Authors: Lide Arana, Io-guané Rivera, Marta Ordoñez, Miguel Trueba, Patricia Gangoiti, Alberto Ouro, Antonio Gómez-muñozAbstract:The bioactive sphingolipid Ceramide 1-Phosphate (C1P) is implicated in inflammatory responses and was recently shown to promote cell migration. However, the mechanisms involved in these actions are...
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New insights on the role of Ceramide 1-Phosphate in inflammation
Biochimica et biophysica acta, 2013Co-Authors: Antonio Gómez-muñoz, Io-guané Rivera, Marta Ordoñez, Patricia Gangoiti, Alberto Ouro, Lide Arana, Miguel TruebaAbstract:Abstract Inflammation is a complex biological process involving a variety of locally produced molecules, as well as different types of white blood cells. Some of the so-called inflammatory mediators include cytokines, chemokines, interleukins, prostaglandins, or bioactive lipids, all of which provide protection from infection and foreign substances, such as bacteria, yeast, viruses or some chemicals. Under some circumstances, however, the organism inappropriately activates the immune system triggering an inflammatory response in the absence of foreign insults thereby leading to the establishment of autoimmune diseases. Therefore, inflammation must be tightly regulated in order to ensure sufficient protection to the organism in the absence of unwanted, and at times dangerous, side effects. Increasing experimental evidence implicates sphingolipids as major inducers of inflammatory responses and regulators of immune cell functions. In particular, Ceramides and sphingosine 1-Phosphate have been extensively implicated in inflammation, and Ceramide 1-Phosphate has also been shown to participate in these processes. The present review highlights novel aspects on the regulation of inflammation by sphingolipids, with special emphasis to the role played by Ceramide 1-phoshate and Ceramide kinase, the enzyme responsible for its biosynthesis, in inflammatory responses.