The Experts below are selected from a list of 2982 Experts worldwide ranked by ideXlab platform
Christophe Vandier - One of the best experts on this subject based on the ideXlab platform.
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hypoxia promotes prostate cancer aggressiveness by upregulating emt activator zeb1 and SK3 channel expression
International Journal of Molecular Sciences, 2020Co-Authors: Fanny Bery, Maxime Guéguinou, Christophe Vandier, Marie Potiercartereau, Sana Kouba, Sandy Figiel, Delphine Fontaine, Roseline Guibon, Franck Bruyere, Gaelle FromontAbstract:Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca2+-activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.
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glyco phospho glycero ether lipid as modulator of SK3 ion channel and SK3 dependent cancer cell migration
Phosphorus Sulfur and Silicon and The Related Elements, 2016Co-Authors: Charlotte M Sevrain, Aurélie Chantôme, Christophe Vandier, Marie Potiercartereau, Wilfried Berthe, Ana Bouchet, Jeanpierre Haelters, Helene Couthongourves, Paulalain JaffresAbstract:GRAPHICAL ABSTRACTAbstract. In this short review paper we reports our efforts to design new inhibitors of SK3 ion channel that are involved in cancer cell migration and metastases formation. The originality of the new SK3 inhibitors comes from their amphiphilic nature and contrast form others inhibitors that are peptides or heterocyclic compounds. We found that ether lipids and ether phospho-glyco-lipids are indeed efficient to modulate SK3 ion channel that consequently reduced cancer cell migration (in vitro assays) and abolished the formation of bone metastases in a murine model of breast cancer.
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new disaccharide based ether lipids as SK3 ion channel inhibitors
ChemMedChem, 2016Co-Authors: Wilfried Berthe, Maxime Guéguinou, Aurélie Chantôme, Marie Potiercartereau, Charlotte M Sevrain, Ana Bouchet, Yann Fourbon, Jeanpierre Haelters, Helene Couthongourves, Christophe VandierAbstract:: The SK3 potassium channel is involved in the development of bone metastasis and in the settlement of cancer cells in Ca(2+) -rich environments. Ohmline, which is a lactose-based glycero-ether lipid, is a lead compound that decreases SK3 channel activity and consequently limits the migration of SK3-expressing cells. Herein we report the synthesis of three new ohmline analogues in which the connection of the disaccharide moieties (1→6 versus 1→4) and the stereochemistry of the glycosyl linkage was studied. Compound 2 [3-(hexadecyloxy)-2-methoxypropyl-6-O-α-d-glucopyranosyl-β-d-galactopyranoside], which possesses an α-glucopyranosyl-(1→6)-β-galactopyranosyl moiety, was found to decrease SK3 current amplitude (70 % inhibition at 10 μm), displace SK3 protein outside caveolae, and decrease constitutive Ca(2+) entry (50 % inhibition at 300 nm) and SK3-dependent cell migration (30 % at 300 nm) at a level close to that of the benchmark compound ohmline. Compound 2, which decreases the activity of SK3 channel (but not SK2 channel), is a new drug candidate to reduce cancer cell migration and to prevent bone metastasis.
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cAMP–PKA inhibition of SK3 channel reduced both Ca^2+ entry and cancer cell migration by regulation of SK3–Orai1 complex
Pflügers Archiv - European Journal of Physiology, 2014Co-Authors: Lucie Clarysse, Maxime Guéguinou, Marie Potier-cartereau, Grégoire Vandecasteele, Philippe Bougnoux, Stephan Chevalier, Aurélie Chantôme, Christophe VandierAbstract:SK3 channel mediates the migration of various cancer cells. When expressed in breast cancer cells, SK3 channel forms a complex with Orai1, a voltage-independent Ca^2+ channel. This SK3–Orai1 complex associates within lipid rafts where it controls a constitutive Ca^2+ entry leading to cancer cell migration and bone metastases development. Since cAMP was found to modulate breast cancer cell migration, we hypothesized that this could be explained by a modulation of SK3 channel activity. Herein, we study the regulation of SK3 channel by the cAMP–PKA pathway and the consequences for SK3-dependent Ca^2+ entry and cancer cell migration. We established that the beta-adrenergic receptor agonist, isoprenaline, or the direct adenylyl cyclase activator forskolin alone or in combination with the PDE4 inhibitor, CI-1044, decreased SK3 channel activity without modifying the expression of SK3 protein at the plasma membrane. Forskolin and CI-1044 reduced the SK3-dependent constitutive Ca^2+ entry and the SK3-dependent migration of MDA-MB-435s cells. PKA inhibition with KT 5720 reduced: (1) the effect of forskolin and CI-1044 by 50 % on Ca^2+ entry and (2) SK3 activity by inhibiting the serine phosphorylation of SK3. These cAMP-elevating agents displaced Orai1 protein outside lipid rafts in contrast to SK3, which remained in the lipid rafts fractions. All together, these results show that activation of the cAMP–PKA pathway decreases SK3 channel and SK3–Orai1 complex activities, leading to a decrease in both Ca^2+ entry and cancer cell migration. This work supports the potential use of cAMP-elevating agents to reduce cancer cell migration and may provide novel opportunities to address/prevent bone metastasis.
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digalactosyl glycero ether lipid synthetic approaches and evaluation as SK3 channel inhibitor
Organic and Biomolecular Chemistry, 2013Co-Authors: Charlotte M Sevrain, Maxime Guéguinou, Aurélie Chantôme, Marie Potiercartereau, Jeanpierre Haelters, Helene Couthongourves, Christophe VandierAbstract:The recent discoveries of the involvement of SK3 channel in some cell motility mechanisms occurring in cancer disease have opened up the way to the synthesis of inhibitors that could reduce metastasis formation. On the basis of our recent previous works showing that both lactose-glycero-ether lipid (Ohmline) and some phosphate analogues (GPGEL) were efficient compounds to modulate SK3 channel activity, the present study, which found its inspiration in the structure of the natural glycolipid DiGalactosylDiacylGlycerol (DGDG), reports the incorporation of a digalactosyl moiety (α-galactopyranosyl-(1→6)-β-galactopyranosyl-) as the polar head of a glycero ether lipid. For the construction of the digalactosyl fragment, two synthetic approaches were compared. The standard strategy which is based on the use of the benzyl protecting group to produce 1→6 disaccharide unit, was compared with a second method that made use of the trimethylsilyl moiety as a protecting group. This second strategy, which is applied for the first time to the synthesis of (1→6)-disaccharide unit, presents a net advantage in terms of efficacy (better global yield) and cost. Finally, compound 16, which is characterized by a (1→6) DiGalactosyl unit (DG) as the polar head of the amphiphilic structure, was tested as a modulator of the SK3 channel activity. Patch-clamp experiments have shown that compound 16 reduced SK3 currents (−28.2 ± 2.0% at 5 μM) and cell migration assays performed at 300 nM have shown a reduction of cell migration (SK3 + HEK293T) by 19.6 ± 2.7%.
Aurélie Chantôme - One of the best experts on this subject based on the ideXlab platform.
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Cancer Cell Migration and Bone Metastases Orai1 Complex in Human - Pivotal Role of the Lipid Raft SK3
2020Co-Authors: Aurélie Chantôme, Marie Potier-cartereau, Lucie ClarysseAbstract:Abstract The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical stepin metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly associated withbone metastasis. The SK3 channel was shown to control constitutive Ca 2þ entry and cancer cell migrationthrough an interaction with the Ca 2þ channel Orai1. We found that the SK3 channel triggers an associationwith the Orai1 channel within lipid rafts. This localization of an SK3–Orai1 complex seemed essential tocontrol cancer cell migration. This suggests that theformation of this complex in lipid rafts is a gain-of-function, because we showed that none of the individual proteins were able to promote the completephenotype. We identified the alkyl-lipid Ohmline as a disrupting agent for SK3–Orai1 lipid raft localization.Upon Ohmline treatment, the SK3–Orai1 complex moved away from lipid rafts, and SK3-dependent Ca 2þ entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 inprimary human tumors and bone metastases further emphasized the clinical relevance of our observations.Targeting SK3–Orai1 in lipid rafts may inaugurate innovative approaches to inhibit bone metastases.CancerRes; 73(15); 1–10. 2013 AACR.
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lipidic synthetic alkaloids as SK3 channel modulators synthesis and biological evaluation of 2 substituted tetrahydropyridine derivatives with potential anti metastatic activity
European Journal of Medicinal Chemistry, 2020Co-Authors: Sana Kouba, Aurélie Chantôme, Julien Braire, Romain Felix, Paulalain Jaffres, Jacques Lebreton, Didier Dubreuil, Muriel Pipelier, Xuexin Zhang, Mohamed TrebakAbstract:Abstract Small Conductance Calcium (Ca2+)-activated potassium (K+) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In this study, we illustrated the synthesis of new families of lipophilic pyridine and tetrahydropyridine derivatives designed as potential modulators of SK3 channel. The toxicity of the newly synthesized compounds and their migration effects were evaluated on the breast cancer cell line MDA-MB-435s. Two molecules (7a and 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ entry. Current measurements showed that these compounds are more likely SK3-selective. Taken all together these results suggest that such molecules could be considered as promising anti-metastatic drugs in breast cancer.
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the sigmar1 chaperone drives breast and colorectal cancer cell migration by tuning SK3 dependent ca2 plus homeostasis
Oncogene, 2017Co-Authors: Maxime Guéguinou, Lucie Clarysse, Aurélie Chantôme, Marie Potiercartereau, Alban Girault, D Crottes, Raphael Rapettimauss, Y Fourbon, Pascal Jezequel, Catherine GuerincharbonnelAbstract:The remodeling of calcium homeostasis contributes to the cancer hallmarks and the molecular mechanisms involved in calcium channel regulation in tumors remain to be characterized. Here, we report that SigmaR1, a stress-activated chaperone, is required to increase calcium influx by triggering the coupling between SK3, a Ca2+-activated K+ channel (KCNN3) and the voltage-independent calcium channel Orai1. We show that SigmaR1 physically binds SK3 in BC cells. Inhibition of SigmaR1 activity, either by molecular silencing or by the use of sigma ligand (igmesine), decreased SK3 current and Ca2+ entry in breast cancer (BC) and colorectal cancer (CRC) cells. Interestingly, SigmaR1 inhibition diminished SK3 and/or Orai1 levels in lipid nanodomains isolated from BC cells. Analyses of tissue microarray from CRC patients showed higher SigmaR1 expression levels in cancer samples and a correlation with tumor grade. Moreover, the exploration of a cohort of 4937 BC patients indicated that high expression of SigmaR1 and Orai1 channels was significantly correlated to a lower overall survival. As the SK3/Orai1 tandem drives invasive process in CRC and bone metastasis progression in BC, our results may inaugurate innovative therapeutic approaches targeting SigmaR1 to control the remodeling of Ca2+ homeostasis in epithelial cancers.
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glyco phospho glycero ether lipid as modulator of SK3 ion channel and SK3 dependent cancer cell migration
Phosphorus Sulfur and Silicon and The Related Elements, 2016Co-Authors: Charlotte M Sevrain, Aurélie Chantôme, Christophe Vandier, Marie Potiercartereau, Wilfried Berthe, Ana Bouchet, Jeanpierre Haelters, Helene Couthongourves, Paulalain JaffresAbstract:GRAPHICAL ABSTRACTAbstract. In this short review paper we reports our efforts to design new inhibitors of SK3 ion channel that are involved in cancer cell migration and metastases formation. The originality of the new SK3 inhibitors comes from their amphiphilic nature and contrast form others inhibitors that are peptides or heterocyclic compounds. We found that ether lipids and ether phospho-glyco-lipids are indeed efficient to modulate SK3 ion channel that consequently reduced cancer cell migration (in vitro assays) and abolished the formation of bone metastases in a murine model of breast cancer.
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new disaccharide based ether lipids as SK3 ion channel inhibitors
ChemMedChem, 2016Co-Authors: Wilfried Berthe, Maxime Guéguinou, Aurélie Chantôme, Marie Potiercartereau, Charlotte M Sevrain, Ana Bouchet, Yann Fourbon, Jeanpierre Haelters, Helene Couthongourves, Christophe VandierAbstract:: The SK3 potassium channel is involved in the development of bone metastasis and in the settlement of cancer cells in Ca(2+) -rich environments. Ohmline, which is a lactose-based glycero-ether lipid, is a lead compound that decreases SK3 channel activity and consequently limits the migration of SK3-expressing cells. Herein we report the synthesis of three new ohmline analogues in which the connection of the disaccharide moieties (1→6 versus 1→4) and the stereochemistry of the glycosyl linkage was studied. Compound 2 [3-(hexadecyloxy)-2-methoxypropyl-6-O-α-d-glucopyranosyl-β-d-galactopyranoside], which possesses an α-glucopyranosyl-(1→6)-β-galactopyranosyl moiety, was found to decrease SK3 current amplitude (70 % inhibition at 10 μm), displace SK3 protein outside caveolae, and decrease constitutive Ca(2+) entry (50 % inhibition at 300 nm) and SK3-dependent cell migration (30 % at 300 nm) at a level close to that of the benchmark compound ohmline. Compound 2, which decreases the activity of SK3 channel (but not SK2 channel), is a new drug candidate to reduce cancer cell migration and to prevent bone metastasis.
John P. Adelman - One of the best experts on this subject based on the ideXlab platform.
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endothelial SK3 channel associated ca2 microdomains modulate blood pressure
American Journal of Physiology-heart and Circulatory Physiology, 2016Co-Authors: David S Weber, James Maylie, Mark S Taylor, Mary I Townsley, Brian S Comer, John P. AdelmanAbstract:We used mice with specific deletion of the endothelial small-conductance Ca2+-activated potassium 3 (SK3) channel in vascular endothelium to study the SK3 subcellular localization, interaction with...
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differential subcellular localization of SK3 containing channels in the hippocampus
European Journal of Neuroscience, 2014Co-Authors: Carmen Ballesterosmerino, John P. Adelman, Masahiko Watanabe, Ryuichi Shigemoto, Yugo Fukazawa, Rafael LujanAbstract:: Small-conductance, Ca(2+) -activated K(+) (SK) channels are expressed in the hippocampus where they regulate synaptic responses, plasticity, and learning and memory. To investigate the expression of SK3 (KCNN3) subunits, we determined the developmental profile and subcellular distribution of SK3 in the developing mouse hippocampus using western blots, immunohistochemistry and high-resolution immunoelectron microscopy. The results showed that SK3 expression increased during postnatal development, and that the localization of SK3 changed from being mainly associated with the endoplasmic reticulum and intracellular sites during the first postnatal week to being progressively concentrated in dendritic spines during later stages. In the adult, SK3 was localized mainly in postsynaptic compartments, both at extrasynaptic sites and along the postsynaptic density of excitatory synapses. Double labelling showed that SK3 co-localized with SK2 (KCNN2) and with N-methyl-D-aspartate receptors. Finally, quantitative analysis of SK3 density revealed two subcellular distribution patterns in different hippocampal layers, with SK3 being unevenly distributed in CA1 region of the hippocampus pyramidal cells and homogeneously distributed in dentate gyrus granule cells. Our results revealed a complex cell surface distribution of SK3-containing channels and a distinct developmental program that may influence different hippocampal functions.
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critical roles of a small conductance ca2 activated k channel SK3 in the repolarization process of atrial myocytes
Cardiovascular Research, 2014Co-Authors: Xiao Dong Zhang, John P. Adelman, Valeriy Timofeyev, Chris T Bond, Ning Li, Daimin Zhang, Richard E Myers, Anil Singapuri, Deborah K LieuAbstract:Aims Small conductance Ca2+-activated K+ channels (KCa2 or SK channels) have been reported in excitable cells, where they aid in integrating changes in intracellular Ca2+ (![Graphic][1] ) with membrane potentials. We have recently reported the functional expression of SK channels in human and mouse cardiac myocytes. Additionally, we have found that the channel is highly expressed in atria compared with the ventricular myocytes. We demonstrated that human cardiac myocytes expressed all three members of SK channels (SK1, 2, and 3); moreover, the different members are capable of forming heteromultimers. Here, we directly tested the contribution of SK3 to the overall repolarization of atrial action potentials. Methods and results We took advantage of a mouse model with site-specific insertion of a tetracycline-based genetic switch in the 5′ untranslated region of the KCNN3 (SK3 channel) gene ( SK3T/T ). The gene-targeted animals overexpress the SK3 channel without interfering with the normal profile of SK3 expression. Whole-cell, patch-clamp techniques show a significant shortening of the action potential duration mainly at 90% repolarization (APD90) in atrial myocytes from the homozygous SK3T/T animals. Conversely, treatment with dietary doxycycline results in a significant prolongation of APD90 in atrial myocytes from SK3T/T animals. We further demonstrate that the shortening of APDs in SK3 overexpression mice predisposes the animals to inducible atrial arrhythmias. Conclusion SK3 channel contributes importantly towards atrial action potential repolarization. Our data suggest the important role of the SK3 isoform in atrial myocytes. [1]: /embed/inline-graphic-1.gif
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critical roles of SK3 calcium activated potassium channels in the repolarization of atrial myocytes
Biophysical Journal, 2014Co-Authors: Xiao Dong Zhang, John P. Adelman, Valeriy Timofeyev, Chris T Bond, Ning Li, Daimin Zhang, Richard E Myers, Anil Singapuri, Deborah K Lieu, Nipavan ChiamvimonvatAbstract:Small conductance Ca2+-activated K+ channels (SK channels) have been first identified in central nervous system, where they aid in integrating changes in intracellular Ca2+ with the intrinsic excitability of neurons and affect the synaptic transmission and plasticity. We have demonstrated that three members of SK channel family (SK1, SK2 and SK3) are present in human and mouse cardiac myocytes and contribute significantly to the repolarization process in both mouse and human atria. Moreover, the three members can heteromultimerize to form functional channels. In this study, we directly tested the contribution of SK3 channels to the overall repolarization of atrial action potentials. We used a mouse model with site-specific insertion of a tetracycline-based genetic switch in the 5' untranslated region of the KCNN3 (SK3 channel) gene so that SK3 expression could be decreased by dietary doxycycline administration without interfering with the normal profile of SK3 expression. Whole-cell patch-clamp recording showed a significant shortening of the action potential duration mainly at 90% repolarization (APD90) in atrial myocytes from the homozygous SK3T/T animals. Conversely, treatment with dietary doxycycline results in a significant prolongation of APD90 in atrial myocytes from SK3T/T animals. We further demonstrated that the shortening of action potential durations in SK3 over-expression mice predisposes the animals to inducible atrial arrhythmias. In conclusion, SK3 contributes toward atrial action potential repolarization, suggesting the pivotal role of the SK channels in atrial myocytes.
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sk2 and SK3 expression differentially affect firing frequency and precision in dopamine neurons
Neuroscience, 2012Co-Authors: Jason Deignan, James Maylie, Chris T Bond, Masahiko Watanabe, Rafael Lujan, Arthur Riegel, John T Williams, John P. AdelmanAbstract:Abstract The firing properties of dopamine (DA) neurons in the substantia nigra (SN) pars compacta are strongly influenced by the activity of apamin-sensitive small conductance Ca 2+ -activated K + (SK) channels. Of the three SK channel genes expressed in central neurons, only SK3 expression has been identified in DA neurons. The present findings show that SK2 was also expressed in DA neurons. Immuno-electron microscopy (iEM) showed that SK2 was primarily expressed in the distal dendrites, while SK3 was heavily expressed in the soma and, to a lesser extent, throughout the dendritic arbor. Electrophysiological recordings of the effects of the SK channel blocker apamin on DA neurons from wild type and SK −/− mice show that SK2-containing channels contributed to the precision of action potential (AP) timing, while SK3-containing channels influenced AP frequency. The expression of SK2 in DA neurons may endow distinct signaling and subcellular localization to SK2-containing channels.
Philippe Bougnoux - One of the best experts on this subject based on the ideXlab platform.
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cAMP–PKA inhibition of SK3 channel reduced both Ca^2+ entry and cancer cell migration by regulation of SK3–Orai1 complex
Pflügers Archiv - European Journal of Physiology, 2014Co-Authors: Lucie Clarysse, Maxime Guéguinou, Marie Potier-cartereau, Grégoire Vandecasteele, Philippe Bougnoux, Stephan Chevalier, Aurélie Chantôme, Christophe VandierAbstract:SK3 channel mediates the migration of various cancer cells. When expressed in breast cancer cells, SK3 channel forms a complex with Orai1, a voltage-independent Ca^2+ channel. This SK3–Orai1 complex associates within lipid rafts where it controls a constitutive Ca^2+ entry leading to cancer cell migration and bone metastases development. Since cAMP was found to modulate breast cancer cell migration, we hypothesized that this could be explained by a modulation of SK3 channel activity. Herein, we study the regulation of SK3 channel by the cAMP–PKA pathway and the consequences for SK3-dependent Ca^2+ entry and cancer cell migration. We established that the beta-adrenergic receptor agonist, isoprenaline, or the direct adenylyl cyclase activator forskolin alone or in combination with the PDE4 inhibitor, CI-1044, decreased SK3 channel activity without modifying the expression of SK3 protein at the plasma membrane. Forskolin and CI-1044 reduced the SK3-dependent constitutive Ca^2+ entry and the SK3-dependent migration of MDA-MB-435s cells. PKA inhibition with KT 5720 reduced: (1) the effect of forskolin and CI-1044 by 50 % on Ca^2+ entry and (2) SK3 activity by inhibiting the serine phosphorylation of SK3. These cAMP-elevating agents displaced Orai1 protein outside lipid rafts in contrast to SK3, which remained in the lipid rafts fractions. All together, these results show that activation of the cAMP–PKA pathway decreases SK3 channel and SK3–Orai1 complex activities, leading to a decrease in both Ca^2+ entry and cancer cell migration. This work supports the potential use of cAMP-elevating agents to reduce cancer cell migration and may provide novel opportunities to address/prevent bone metastasis.
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camp pka inhibition of SK3 channel reduced both ca2 entry and cancer cell migration by regulation of SK3 orai1 complex
Pflügers Archiv: European Journal of Physiology, 2014Co-Authors: Lucie Clarysse, Maxime Guéguinou, Grégoire Vandecasteele, Philippe Bougnoux, Marie PotiercartereauAbstract:SK3 channel mediates the migration of various cancer cells. When expressed in breast cancer cells, SK3 channel forms a complex with Orai1, a voltage-independent Ca2+ channel. This SK3–Orai1 complex associates within lipid rafts where it controls a constitutive Ca2+ entry leading to cancer cell migration and bone metastases development. Since cAMP was found to modulate breast cancer cell migration, we hypothesized that this could be explained by a modulation of SK3 channel activity. Herein, we study the regulation of SK3 channel by the cAMP–PKA pathway and the consequences for SK3-dependent Ca2+ entry and cancer cell migration. We established that the beta-adrenergic receptor agonist, isoprenaline, or the direct adenylyl cyclase activator forskolin alone or in combination with the PDE4 inhibitor, CI-1044, decreased SK3 channel activity without modifying the expression of SK3 protein at the plasma membrane. Forskolin and CI-1044 reduced the SK3-dependent constitutive Ca2+ entry and the SK3-dependent migration of MDA-MB-435s cells. PKA inhibition with KT 5720 reduced: (1) the effect of forskolin and CI-1044 by 50 % on Ca2+ entry and (2) SK3 activity by inhibiting the serine phosphorylation of SK3. These cAMP-elevating agents displaced Orai1 protein outside lipid rafts in contrast to SK3, which remained in the lipid rafts fractions. All together, these results show that activation of the cAMP–PKA pathway decreases SK3 channel and SK3–Orai1 complex activities, leading to a decrease in both Ca2+ entry and cancer cell migration. This work supports the potential use of cAMP-elevating agents to reduce cancer cell migration and may provide novel opportunities to address/prevent bone metastasis.
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the SK3 kca2 3 potassium channel is a new cellular target for edelfosine
British Journal of Pharmacology, 2011Co-Authors: M Potier, Philippe Bougnoux, Aurélie Chantôme, Alban Girault, Virginie Joulin, Sebastien Roger, Pierre Besson, Marielise Jourdan, Jeanyves Leguennec, Christophe VandierAbstract:BACKGROUND AND PURPOSE The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (edelfosine) is an ether-linked phospholipid with promising anti-cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function. EXPERIMENTAL APPROACH Using cell migration-proliferation assays, patch clamp, spectrofluorimetry and 125I-Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA-MB-435s cells, mediated by the small conductance Ca2+-activated K+ channel, SK3/KCa2.3. KEY RESULTS Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/KCa2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit 125I-Apamin binding to this SKCa channel; rather, it reduced the calcium sensitivity of SK3/KCa2.3 channel and dramatically decreased intracellular Ca2+ concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SKCa channel blockers. In contrast, K+ channel openers prevented edelfosine-induced anti-migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA-MB-435s cell migration. In contrast, transient expression of SK3/KCa2.3 protein in a SK3/KCa2.3-deficient cell line increased cell migration and made these cells responsive to edelfosine. CONCLUSIONS AND IMPLICATIONS Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/KCa2.3 channels and provide insights into the future development of a new class of migration-targeted, anti-cancer agents.
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The SK3/KCa2.3 potassium channel is a new cellular target for edelfosine
British Journal of Pharmacology, 2010Co-Authors: M Potier, Philippe Bougnoux, Aurélie Chantôme, Alban Girault, Virginie Joulin, Sebastien Roger, Pierre Besson, Marielise Jourdan, Jeanyves Leguennec, Christophe VandierAbstract:BACKGROUND AND PURPOSE The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (edelfosine) is an ether-linked phospholipid with promising anti-cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function. EXPERIMENTAL APPROACH Using cell migration-proliferation assays, patch clamp, spectrofluorimetry and 125I-Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA-MB-435s cells, mediated by the small conductance Ca2+-activated K+ channel, SK3/KCa2.3. KEY RESULTS Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/KCa2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit 125I-Apamin binding to this SKCa channel; rather, it reduced the calcium sensitivity of SK3/KCa2.3 channel and dramatically decreased intracellular Ca2+ concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SKCa channel blockers. In contrast, K+ channel openers prevented edelfosine-induced anti-migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA-MB-435s cell migration. In contrast, transient expression of SK3/KCa2.3 protein in a SK3/KCa2.3-deficient cell line increased cell migration and made these cells responsive to edelfosine. CONCLUSIONS AND IMPLICATIONS Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/KCa2.3 channels and provide insights into the future development of a new class of migration-targeted, anti-cancer agents.
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altered SK3 kca2 3 mediated migration in adenomatous polyposis coli apc mutated mouse colon epithelial cells
Biochemical and Biophysical Research Communications, 2010Co-Authors: Marie Potier, Philippe Bougnoux, Aurélie Chantôme, Christophe Vandier, Truong An Tran, Alban Girault, Virginie Joulin, Fabrice PierreAbstract:Abstract Lost of adenomatous polyposis coli gene (Apc) disturbs the migration of intestinal epithelial cells but the mechanisms have not been fully characterized. Since we have demonstrated that SK3/KCa2.3 channel promotes cancer cell migration, we hypothesized that Apc mutation may affect SK3/KCa2.3 channel-mediated colon epithelial cell motility. We report evidence that SK3/KCa2.3 channel promotes colon epithelial cells motility. Following Apc mutation SK3/KCa2.3 expression is largely reduced leading to a suppression of the SK3/KCa2.3 channel mediated-cell migration. Our findings reveal a previously unknown function of the SK3/KCa2.3 channel in epithelial colonic cells, and suggest that Apc is a powerful regulator SK3/KCa2.3 channel.
Marie Potiercartereau - One of the best experts on this subject based on the ideXlab platform.
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hypoxia promotes prostate cancer aggressiveness by upregulating emt activator zeb1 and SK3 channel expression
International Journal of Molecular Sciences, 2020Co-Authors: Fanny Bery, Maxime Guéguinou, Christophe Vandier, Marie Potiercartereau, Sana Kouba, Sandy Figiel, Delphine Fontaine, Roseline Guibon, Franck Bruyere, Gaelle FromontAbstract:Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca2+-activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.
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the sigmar1 chaperone drives breast and colorectal cancer cell migration by tuning SK3 dependent ca2 plus homeostasis
Oncogene, 2017Co-Authors: Maxime Guéguinou, Lucie Clarysse, Aurélie Chantôme, Marie Potiercartereau, Alban Girault, D Crottes, Raphael Rapettimauss, Y Fourbon, Pascal Jezequel, Catherine GuerincharbonnelAbstract:The remodeling of calcium homeostasis contributes to the cancer hallmarks and the molecular mechanisms involved in calcium channel regulation in tumors remain to be characterized. Here, we report that SigmaR1, a stress-activated chaperone, is required to increase calcium influx by triggering the coupling between SK3, a Ca2+-activated K+ channel (KCNN3) and the voltage-independent calcium channel Orai1. We show that SigmaR1 physically binds SK3 in BC cells. Inhibition of SigmaR1 activity, either by molecular silencing or by the use of sigma ligand (igmesine), decreased SK3 current and Ca2+ entry in breast cancer (BC) and colorectal cancer (CRC) cells. Interestingly, SigmaR1 inhibition diminished SK3 and/or Orai1 levels in lipid nanodomains isolated from BC cells. Analyses of tissue microarray from CRC patients showed higher SigmaR1 expression levels in cancer samples and a correlation with tumor grade. Moreover, the exploration of a cohort of 4937 BC patients indicated that high expression of SigmaR1 and Orai1 channels was significantly correlated to a lower overall survival. As the SK3/Orai1 tandem drives invasive process in CRC and bone metastasis progression in BC, our results may inaugurate innovative therapeutic approaches targeting SigmaR1 to control the remodeling of Ca2+ homeostasis in epithelial cancers.
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glyco phospho glycero ether lipid as modulator of SK3 ion channel and SK3 dependent cancer cell migration
Phosphorus Sulfur and Silicon and The Related Elements, 2016Co-Authors: Charlotte M Sevrain, Aurélie Chantôme, Christophe Vandier, Marie Potiercartereau, Wilfried Berthe, Ana Bouchet, Jeanpierre Haelters, Helene Couthongourves, Paulalain JaffresAbstract:GRAPHICAL ABSTRACTAbstract. In this short review paper we reports our efforts to design new inhibitors of SK3 ion channel that are involved in cancer cell migration and metastases formation. The originality of the new SK3 inhibitors comes from their amphiphilic nature and contrast form others inhibitors that are peptides or heterocyclic compounds. We found that ether lipids and ether phospho-glyco-lipids are indeed efficient to modulate SK3 ion channel that consequently reduced cancer cell migration (in vitro assays) and abolished the formation of bone metastases in a murine model of breast cancer.
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new disaccharide based ether lipids as SK3 ion channel inhibitors
ChemMedChem, 2016Co-Authors: Wilfried Berthe, Maxime Guéguinou, Aurélie Chantôme, Marie Potiercartereau, Charlotte M Sevrain, Ana Bouchet, Yann Fourbon, Jeanpierre Haelters, Helene Couthongourves, Christophe VandierAbstract:: The SK3 potassium channel is involved in the development of bone metastasis and in the settlement of cancer cells in Ca(2+) -rich environments. Ohmline, which is a lactose-based glycero-ether lipid, is a lead compound that decreases SK3 channel activity and consequently limits the migration of SK3-expressing cells. Herein we report the synthesis of three new ohmline analogues in which the connection of the disaccharide moieties (1→6 versus 1→4) and the stereochemistry of the glycosyl linkage was studied. Compound 2 [3-(hexadecyloxy)-2-methoxypropyl-6-O-α-d-glucopyranosyl-β-d-galactopyranoside], which possesses an α-glucopyranosyl-(1→6)-β-galactopyranosyl moiety, was found to decrease SK3 current amplitude (70 % inhibition at 10 μm), displace SK3 protein outside caveolae, and decrease constitutive Ca(2+) entry (50 % inhibition at 300 nm) and SK3-dependent cell migration (30 % at 300 nm) at a level close to that of the benchmark compound ohmline. Compound 2, which decreases the activity of SK3 channel (but not SK2 channel), is a new drug candidate to reduce cancer cell migration and to prevent bone metastasis.
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camp pka inhibition of SK3 channel reduced both ca2 entry and cancer cell migration by regulation of SK3 orai1 complex
Pflügers Archiv: European Journal of Physiology, 2014Co-Authors: Lucie Clarysse, Maxime Guéguinou, Grégoire Vandecasteele, Philippe Bougnoux, Marie PotiercartereauAbstract:SK3 channel mediates the migration of various cancer cells. When expressed in breast cancer cells, SK3 channel forms a complex with Orai1, a voltage-independent Ca2+ channel. This SK3–Orai1 complex associates within lipid rafts where it controls a constitutive Ca2+ entry leading to cancer cell migration and bone metastases development. Since cAMP was found to modulate breast cancer cell migration, we hypothesized that this could be explained by a modulation of SK3 channel activity. Herein, we study the regulation of SK3 channel by the cAMP–PKA pathway and the consequences for SK3-dependent Ca2+ entry and cancer cell migration. We established that the beta-adrenergic receptor agonist, isoprenaline, or the direct adenylyl cyclase activator forskolin alone or in combination with the PDE4 inhibitor, CI-1044, decreased SK3 channel activity without modifying the expression of SK3 protein at the plasma membrane. Forskolin and CI-1044 reduced the SK3-dependent constitutive Ca2+ entry and the SK3-dependent migration of MDA-MB-435s cells. PKA inhibition with KT 5720 reduced: (1) the effect of forskolin and CI-1044 by 50 % on Ca2+ entry and (2) SK3 activity by inhibiting the serine phosphorylation of SK3. These cAMP-elevating agents displaced Orai1 protein outside lipid rafts in contrast to SK3, which remained in the lipid rafts fractions. All together, these results show that activation of the cAMP–PKA pathway decreases SK3 channel and SK3–Orai1 complex activities, leading to a decrease in both Ca2+ entry and cancer cell migration. This work supports the potential use of cAMP-elevating agents to reduce cancer cell migration and may provide novel opportunities to address/prevent bone metastasis.