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12 results on '"Cancéropôle du Grand Ouest"'

1. NALCN-mediated sodium influx confers metastatic prostate cancer cell invasiveness

Author

Folcher, Antoine, Gordienko, Dmitri, Iamshanova, Oksana, Bokhobza, Alexandre, Shapovalov, George, Kannancheri-Puthooru, Dheeraj, Mariot, Pascal, Allart, Laurent, Desruelles, Emilie, Spriet, Corentin, Diez, Raquel, Oullier, Thibauld, Marionneau-Lambot, Séverine, Brisson, Lucie, Geraci, Sandra, Impheng, Hathaichanok, Lehen'Kyi, V'Yacheslav, Haustrate, Aurélien, Mihalache, Adriana, Gosset, Pierre, Chadet, Stéphanie, Retif, Stéphanie, Laube, Maryline, Sobilo, Julien, Lerondel, Stéphanie, Villari, Giulia, Serini, Guido, Pla, Alessandra Fiorio, Roger, Sébastien, Fromont-Hankard, Gaelle, Djamgoz, Mustafa, Clezardin, Philippe, Monteil, Arnaud, Prevarskaya, Natalia, Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 (PHYCELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Universidad de Extremadura - University of Extremadura (UEX), Cancéropôle du Grand Ouest, Université de Nantes (UN), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Naresuan University, Université catholique de Lille (UCL), EA4245 - Transplantation, Immunologie, Inflammation [Tours] (T2i), Université de Tours (UT), Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Centre d'Imagerie du Petit Animal (CIPA), Université d'Orléans (UO), Università degli studi di Torino = University of Turin (UNITO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imperial College London, Cyprus International University, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), LabEx Ion Channels Science and Therapeutics [France], and ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011)

Subjects
Sodium leak channel, calcium oscillations, invasion, oncochannelopathy, vesicle secretion, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology
Abstract

International audience; There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na+ /Ca2+ signature required for persistent invasion. We identify the Na+ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na+ influx into cancer cells maintains intracellular Ca2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na+ /Ca2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.

Published
2023
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2. 3-Fluoro- and 3,3-Difluoro-3,4-dideoxy-KRN7000 Analogues as New Potent Immunostimulator Agents: Total Synthesis and Biological Evaluation in Human Invariant Natural Killer T Cells and Mice

Author

J.Y. Douillard, Christine Saluzzo, Stéphane Guillarme, Gilles Dujardin, Séverine Marionneau-Lambot, Jézabel Rocher, Jacques Le Pendu, Jean-Yves Le Questel, Michel Evain, Jacques Lebreton, Jean-Cédric Frison, Didier Dubreuil, Mette Diswall, Muriel Pipelier, Thibauld Oullier, Denis Jacquemin, Jérôme Graton, Julie Hunault, Virginie Blot, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Cancéropôle du Grand Ouest, Université de Nantes (UN), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Unité de chimie organique moléculaire et macromoléculaire (UCO2M), Le Mans Université (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut des Matériaux Jean Rouxel (IMN), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Ecole Polytechnique de l'Université de Nantes (EPUN), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
Models, Molecular, Stereochemistry, Antigen presentation, Receptors, Antigen, T-Cell, Antigen-Presenting Cells, Galactosylceramides, 010402 general chemistry, 01 natural sciences, Cell Line, Mice, Structure-Activity Relationship, Th2 Cells, Immune system, Adjuvants, Immunologic, Species Specificity, Antigen, In vivo, Drug Discovery, Animals, Humans, Structure–activity relationship, ComputingMilieux_MISCELLANEOUS, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Protein Stability, 010405 organic chemistry, Chemistry, Hydrogen Bonding, Stereoisomerism, Th1 Cells, In vitro, 0104 chemical sciences, Mice, Inbred C57BL, Biochemistry, CD1D, biology.protein, Natural Killer T-Cells, Molecular Medicine, Female, Antigens, CD1d, Cell activation
Abstract

We propose here the synthesis and biological evaluation of 3,4-dideoxy-GalCer derivatives. The absence of the 3- and 4-hydroxyls on the sphingoid base is combined with the introduction of mono or difluoro substituent at C3 (analogues 8 and 9, respectively) to evaluate their effect on the stability of the ternary CD1d/GalCer/TCR complex which strongly modulate the immune responses. Biological evaluations were performed in vitro on human cells and in vivo in mice and results discussed with support of modeling studies. The fluoro 3,4-dideoxy-GalCer analogues appears as partial agonists compared to KRN7000 for iNKT cell activation, inducing T(H)1 or T(H)2 biases that strongly depend of the mode of antigen presentation, including human vs mouse differences. We evidenced that if a sole fluorine atom is not able to balance the loss of the 3-OH, the presence of a difluorine group at C3 of the sphingosine can significantly restore human iNKT activation.

Published
2012
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3. Pivotal Role of the Lipid Raft SK3-Orai1 Complex in Human Cancer Cell Migration and Bone Metastases

Author

Paul-Alain Jaffrès, Maxime Guéguinou, Christine Collin, Flavie Arbion, Thibauld Oullier, Pierre Besson, Gaëlle Fromont, Christophe Vandier, Jean-Pierre Haelters, Marie Potier-Cartereau, Séverine Marionneau-Lambot, Alban Girault, Jean-Christophe Pages, Virginie Joulin, Lucie Clarysse, Michelle Pinault, Philippe Bougnoux, Aurélie Chantôme, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers, Cancéropôle du Grand Ouest, Université de Nantes (UN), Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'Anatomopathologie [Tours], Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inserm UMR1069, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT)-EA3856, Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Vandier, Christophe, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Patch-Clamp Techniques, ORAI1 Protein, Small-Conductance Calcium-Activated Potassium Channels, Blotting, Western, Mice, Nude, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Metastasis, 03 medical and health sciences, Mice, 0302 clinical medicine, Membrane Microdomains, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Cell Line, Tumor, Medicine, Animals, Humans, Neoplasm Invasiveness, Lipid raft, 030304 developmental biology, 0303 health sciences, business.industry, ORAI1, Colocalization, Bone metastasis, Cell migration, Neoplasms, Experimental, medicine.disease, Immunohistochemistry, Potassium channel, Cell biology, Disease Models, Animal, Oncology, Cell culture, 030220 oncology & carcinogenesis, Female, lipids (amino acids, peptides, and proteins), Calcium Channels, business
Abstract

The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical step in metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly associated with bone metastasis. The SK3 channel was shown to control constitutive Ca2+ entry and cancer cell migration through an interaction with the Ca2+ channel Orai1. We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts. This localization of an SK3–Orai1 complex seemed essential to control cancer cell migration. This suggests that the formation 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 complete phenotype. 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 Ca2+ entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 in primary 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. Cancer Res; 73(15); 4852–61. ©2013 AACR.

Published
2013
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4. Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): potent cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts

Author

Aziz Ouach, Thibauld Oullier, Christiane Guguen-Guillouzo, Sylvain Routier, Rajâa Boulahjar, Gérald Guillaumet, Olivier Lozach, Laurent Meijer, Said Lazar, Chiurato Matteo, Stéphane Bourg, Myriam Ravache, Mohamed Akssira, Séverine Marionneau, Rémy Le Guével, Yves Troin, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Plate-forme ImPACcell (ImPACcell), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancéropole Nord-Ouest, Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), ManRos Therapeutics, Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Chimie, Bioorganique et analytique, Université Hassan II [Casablanca] (UH2MC), Laboratoire de Chimie Physique & de Chimie Bioorganique, URAC 22 (LCPCB), Faculte des sciences et Techniques Mohammedia [Casablanca] (FSTM), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Laboratoire de Chimie des Hétérocycles et des Glucides (LCHG), Ecole Nationale Supérieure de Chimie de Clermont-Ferrand (ENSCCF), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique fonctionnelle, agronomie et santé (GFAS), Cancéropôle du Grand Ouest, Université de Nantes (UN), Phophorylation de protéines et Pathologies Humaines (P3H), Institut de Chimie de Clermont-Ferrand (ICCF), Centre National de la Recherche Scientifique (CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Sigma CLERMONT (Sigma CLERMONT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-SIGMA Clermont (SIGMA Clermont)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff [Roscoff] (SBR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Antineoplastic Agents, Apoptosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 010402 general chemistry, 01 natural sciences, Glycogen Synthase Kinase 3, Mice, Structure-Activity Relationship, Cyclin-dependent kinase, In vivo, GSK-3, Heterocyclic Compounds, Neoplasms, Drug Discovery, Potency, Animals, Humans, Enzyme Inhibitors, Phosphorylation, IC50, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Glycogen Synthase Kinase 3 beta, biology, 010405 organic chemistry, Chemistry, Kinase, Cyclin-dependent kinase 5, Cell Cycle, Cyclin-Dependent Kinase 5, Xenograft Model Antitumor Assays, 0104 chemical sciences, 3. Good health, Human tumor, biology.protein, Molecular Medicine, Female
Abstract

International audience; The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3β in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.

Published
2012
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5. New alkyl-lipid blockers of SK3 channels reduce cancer-cell migration and occurrence of metastasis

Author

Alban Girault, Jean-Pierre Haelters, marie Potier-Cartereau, Aurélie Chantôme, Michelle Pinault, Severine Marionneau-Lambot, Thibauld Oullier, Gaelle Simon, Hélène Couthon, Paul-Alain Jaffres, Bernard Corbel, Philippe Bougnoux, Virginie Joulin, Christophe Vandier, Nutrition, croissance et cancer (U 1069) (N2C), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Cancéropôle du Grand Ouest, Université de Nantes (UN), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vandier, Christophe, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
[SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; Edelfosine is an inhibitor of SK3 channel-mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl-2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamine from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-antimetastatic agent.

Published
2011

6. New alkyl-lipid blockers of SK3 channels reduce cancer cell migration and occurrence of metastasis

Author

Séverine Marionneau-Lambot, Gaëlle Simon, Aurélie Chantôme, Virginie Joulin, Hélène Couthon-Gourvès, Thibauld Oullier, Christophe Vandier, Paul-Alain Jaffrès, Michelle Pinault, Bernard Corbel, Jean-Pierre Haelters, Alban Girault, Marie Potier-Cartereau, Philippe Bougnoux, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherches insulaires et observatoire de l'environnement (CRIOBE), Université de Perpignan Via Domitia (UPVD)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Cancéropôle du Grand Ouest, Université de Nantes (UN), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cancer Research, Small-Conductance Calcium-Activated Potassium Channels, migration, Receptors, G-Protein-Coupled, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cell Movement, Drug Discovery, Lysophosphatidic acid, Enzyme Inhibitors, Receptors, Lysophosphatidic Acid, Protein Kinase C, 0303 health sciences, Molecular Structure, [CHIM.ORGA]Chemical Sciences/Organic chemistry, glycero-lipid, Phospholipid Ethers, 3. Good health, Cell biology, Oncology, Biochemistry, 030220 oncology & carcinogenesis, small hairpin RNA, KCa2.3, Female, Cell Migration Assays, Edelfosine, Small conductance calcium-activated K+, Mice, Nude, Breast Neoplasms, Platelet Membrane Glycoproteins, Biology, Apamin, Multiplicity Of Infection, 03 medical and health sciences, Structure-Activity Relationship, In vivo, Phospholipase C, Cell Line, Tumor, Potassium Channel Blockers, Structure–activity relationship, metastasis, [CHIM]Chemical Sciences, Animals, Humans, Channel blocker, Platelet Activating Factor, Protein kinase C, 030304 developmental biology, Pharmacology, Dose-Response Relationship, Drug, Epithelial Cells, Potential Calcium, chemistry, Glycolipids
Abstract

International audience; Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-antimetastatic agent.

Published
2011
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7. Ranolazine inhibits NaV1.5-mediated breast cancer cell invasiveness and lung colonization

Author

Stephan Chevalier, Virginie Joulin, Jean-Yves Le Guennec, Virginie Driffort, Sébastien Roger, Jean-Christophe Pages, Pierre Besson, Philippe Bougnoux, Christine Collin, Marie-Lise Jourdan, Emeline Bon, Séverine Marionneau-Lambot, Thibauld Oullier, Ludovic Gillet, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancéropôle du Grand Ouest, Université de Nantes (UN), Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Laboratoire de Biochimie et Biologie Moléculaire, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours (UT)

Subjects
Oncology, medicine.medical_specialty, Cancer Research, Short Communication, Cell, Mice, Nude, Ranolazine, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Metastases, Piperazines, NAV1.5 Voltage-Gated Sodium Channel, Extracellular matrix, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, In vivo, Cell Line, Tumor, Internal medicine, medicine, Animals, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Cancer cell invasiveness, Lung, 030304 developmental biology, 0303 health sciences, Cancer, medicine.disease, NaV1.5 voltage-gated sodium channels, In vitro, 3. Good health, medicine.anatomical_structure, Cell culture, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Molecular Medicine, Acetanilides, Female, medicine.drug
Abstract

Background NaV1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients’ death. In breast cancer cells, NaV1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. Findings In this study, we showed that the extinction of NaV1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 μM) inhibited NaV1.5 currents in breast cancer cells and reduced NaV1.5-related cancer cell invasiveness in vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by NaV1.5-expressing human breast cancer cells. Conclusions Taken together, our results demonstrate the importance of NaV1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with NaV activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments. Electronic supplementary material The online version of this article (doi:10.1186/1476-4598-13-264) contains supplementary material, which is available to authorized users.

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8. NALCN-mediated sodium influx confers metastatic prostate cancer cell invasiveness.

Author

Folcher A, Gordienko D, Iamshanova O, Bokhobza A, Shapovalov G, Kannancheri-Puthooru D, Mariot P, Allart L, Desruelles E, Spriet C, Diez R, Oullier T, Marionneau-Lambot S, Brisson L, Geraci S, Impheng H, Lehen'kyi V, Haustrate A, Mihalache A, Gosset P, Chadet S, Retif S, Laube M, Sobilo J, Lerondel S, Villari G, Serini G, Pla AF, Roger S, Fromont-Hankard G, Djamgoz M, Clezardin P, Monteil A, and Prevarskaya N

Subjects
Male, Humans, Ion Channels metabolism, Ion Transport, Membrane Proteins genetics, Membrane Proteins metabolism, Sodium metabolism, Prostatic Neoplasms
Abstract

There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na + /Ca 2+ signature required for persistent invasion. We identify the Na + leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca 2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na + influx into cancer cells maintains intracellular Ca 2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na + /Ca 2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Published
2023
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9. TRPM8 as an Anti-Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination.

Author

Grolez GP, Chinigò G, Barras A, Hammadi M, Noyer L, Kondratska K, Bulk E, Oullier T, Marionneau-Lambot S, Le Mée M, Rétif S, Lerondel S, Bongiovanni A, Genova T, Roger S, Boukherroub R, Schwab A, Fiorio Pla A, and Gkika D

Subjects
Animals, Carcinogenesis metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Humans, Male, Membrane Proteins metabolism, Mice, Neoplasm Metastasis pathology, Prostate pathology, Prostatic Neoplasms metabolism, TRPM Cation Channels genetics, TRPM Cation Channels metabolism
Abstract

In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies. The purpose of this study was to clarify the role played by TRPM8 in PCa progression. We used a prostate orthotopic xenograft mouse model to show that TRPM8 overexpression dramatically limited tumor growth and metastasis dissemination in vivo. Mechanistically, our in vitro data revealed that TRPM8 inhibited tumor growth by affecting the cell proliferation and clonogenic properties of PCa cells. Moreover, TRPM8 impacted metastatic dissemination mainly by impairing cytoskeleton dynamics and focal adhesion formation through the inhibition of the Cdc42, Rac1, ERK, and FAK pathways. Lastly, we proved the in vivo efficiency of a new tool based on lipid nanocapsules containing WS12 in limiting the TRPM8-positive cells' dissemination at metastatic sites. Our work strongly supports the protective role of TRPM8 on PCa progression, providing new insights into the potential application of TRPM8 as a therapeutic target in PCa treatment.

Published
2022
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10. Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo .

Author

Joalland N, Lafrance L, Oullier T, Marionneau-Lambot S, Loussouarn D, Jarry U, and Scotet E

Abstract

Epithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate <35%). Diagnosis of EOC is frequently made at advanced stages and, despite aggressive treatments combining surgery and chemotherapy, fatal relapse rapidly occurs and is accompanied by a peritoneal carcinosis. In this context, novel therapeutical advances are urgently required. Adoptive transfer(s) of immune effector cells, including allogeneic human Vγ9Vδ2 T lymphocytes, represent attractive targets for efficiently and safely tracking tissue-invading tumor cells and controlling tumor dissemination in the organism. Our study describes the establishment of robust and physiological orthotopic model of human EOC in mouse, that includes surgical resection (ovariectomy) and chemotherapy, which are ineluctably accompanied by a fatal peritoneal carcinosis recurrence. Through a complementary set of in vitro and in vivo experiments, we provide here a preclinical proof of interest of the antitumor efficiency of adoptive transfers of allogeneic human Vγ9Vδ2 T lymphocytes against EOC, in association with surgical debulking and standard chemotherapies (i.e., taxanes and platinum salts). Moreover, our results indicate that chemo- and immunotherapies can be combined to improve the antitumor efficiency of immunotherapeutic lines. Altogether, these results further pave the way for next-generation antitumor immunotherapies, based on local administrations of human allogeneic human Vγ9Vδ2 T lymphocytes, in association with standard treatments., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Published
2019
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11. Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism.

Author

Greco MR, Bon E, Rubino R, Guerra L, Bernabe-Garcia M, Cannone S, Cayuela ML, Ciaccia L, Marionneau-Lambot S, Oullier T, Fromont G, Guibon R, Roger S, Reshkin SJ, and Cardone RA

Subjects
Animals, Breast Neoplasms pathology, Cell Line, Tumor, Disease Models, Animal, Female, Gene Expression Regulation, Neoplastic, Humans, Hydrogen-Ion Concentration, Mice, Mutant Proteins metabolism, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphoproteins genetics, Phosphorylation, Signal Transduction, Sodium-Hydrogen Exchanger 1 metabolism, Sodium-Hydrogen Exchangers genetics, Xenograft Model Antitumor Assays, Zebrafish, Breast Neoplasms metabolism, Phenotype, Phosphoproteins metabolism, Sodium-Hydrogen Exchangers metabolism
Abstract

Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Published
2019
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12. SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer.

Author

Bon E, Driffort V, Gradek F, Martinez-Caceres C, Anchelin M, Pelegrin P, Cayuela ML, Marionneau-Lambot S, Oullier T, Guibon R, Fromont G, Gutierrez-Pajares JL, Domingo I, Piver E, Moreau A, Burlaud-Gaillard J, Frank PG, Chevalier S, Besson P, and Roger S

Subjects
Animals, Breast Neoplasms ultrastructure, Cell Line, Tumor, Cell Proliferation, Disease Progression, Down-Regulation genetics, Epithelial Cells metabolism, Extracellular Matrix metabolism, Female, Gene Expression Regulation, Neoplastic, Human Umbilical Vein Endothelial Cells metabolism, Humans, Ion Channel Gating, Mice, Nude, Neoplasm Invasiveness, Neoplasm Metastasis, Prognosis, Protein Subunits metabolism, Sodium Channels metabolism, Voltage-Gated Sodium Channel beta-4 Subunit metabolism, Zebrafish, rhoA GTP-Binding Protein metabolism, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Movement genetics, Genes, Tumor Suppressor, Voltage-Gated Sodium Channel beta-4 Subunit genetics
Abstract

The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed 'mesenchymal' and 'amoeboid', with possible transitions between these modes. Here we show that the SCN4B gene, encoding for the β4 protein, initially characterized as an auxiliary subunit of voltage-gated sodium channels (Na V ) in excitable tissues, is expressed in normal epithelial cells and that reduced β4 protein levels in breast cancer biopsies correlate with high-grade primary and metastatic tumours. In cancer cells, reducing β4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid-mesenchymal hybrid phenotype. This hyperactivated migration is independent of Na V and is prevented by overexpression of the intracellular C-terminus of β4. Conversely, SCN4B overexpression reduces cancer cell invasiveness and tumour progression, indicating that SCN4B/β4 represents a metastasis-suppressor gene.

Published
2016
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