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Jose A, Fernando JJ, Kienesberger PC. Lysophosphatidic acid metabolism and signaling in heart disease. Can J Physiol Pharmacol 2024; 102:685-696. [PMID: 38968609 DOI: 10.1139/cjpp-2024-0077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 07/07/2024]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid that is mainly produced by the secreted lysophospholipase D, autotaxin (ATX), and signals through at least six G protein-coupled receptors (LPA1-6). Extracellular LPA is degraded through lipid phosphate phosphatases (LPP1, LPP2, and LPP3) at the plasmamembrane, terminating LPA receptor signaling. The ATX-LPA-LPP3 pathway is critically involved in a wide range of physiological processes, including cell survival, migration, proliferation, angiogenesis, and organismal development. Similarly, dysregulation of this pathway has been linked to many pathological processes, including cardiovascular disease. This review summarizes and interprets current literature examining the regulation and role of the ATX-LPA-LPP3 axis in heart disease. Specifically, the contribution of altered LPA metabolism via ATX and LPP3 and resulting changes to LPA receptor signaling in obesity cardiomyopathy, cardiac mitochondrial dysfunction, myocardial infarction/ischemia-reperfusion injury, hypertrophic cardiomyopathy, and aortic valve stenosis is discussed.
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Affiliation(s)
- Anu Jose
- Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, Canada
| | - Jeffy J Fernando
- Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, Canada
| | - Petra C Kienesberger
- Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, Canada
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2
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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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3
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Laface C, Ricci AD, Vallarelli S, Ostuni C, Rizzo A, Ambrogio F, Centonze M, Schirizzi A, De Leonardis G, D’Alessandro R, Lotesoriere C, Giannelli G. Autotaxin-Lysophosphatidate Axis: Promoter of Cancer Development and Possible Therapeutic Implications. Int J Mol Sci 2024; 25:7737. [PMID: 39062979 PMCID: PMC11277072 DOI: 10.3390/ijms25147737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/30/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Simona Vallarelli
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Carmela Ostuni
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Alessandro Rizzo
- Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Francesca Ambrogio
- Section of Dermatology and Venereology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Centonze
- Personalized Medicine Laboratory, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Annalisa Schirizzi
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Giampiero De Leonardis
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Rosalba D’Alessandro
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
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4
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Simonetti J, Ficili M, Sgalla G, Richeldi L. Experimental autotaxin inhibitors for the treatment of idiopathic pulmonary fibrosis. Expert Opin Investig Drugs 2024; 33:133-143. [PMID: 38299617 DOI: 10.1080/13543784.2024.2305126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/23/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
INTRODUCTION Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible, and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX-LPAR signaling axis plays an important role in the pathogenesis and the progression of IPF. AREAS COVERED The aim of this review is to provide an update on the available evidence on autotaxin inhibitors in IPF and further details on the ongoing clinical studies involving these molecules. EXPERT OPINION The development of autotaxin inhibitors as a potential therapy for idiopathic pulmonary fibrosis has gained attention due to evidence of their involvement in the disease. Preclinical and early-phase clinical studies have explored these inhibitors' efficacy and safety, offering a novel approach in treating this disease. Combining autotaxin inhibitors with existing anti-fibrotic agents is considered for enhanced therapeutic effects. Large phase III trials assessed Ziritaxestat but yielded disappointing results, highlighting the importance of long-term observation and clinical outcomes in clinical research. Patient stratification and personalized medicine are crucial, as pulmonary fibrosis is a heterogeneous disease. Ongoing research and collaboration are essential for this advancement.
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Affiliation(s)
- Jacopo Simonetti
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marco Ficili
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giacomo Sgalla
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luca Richeldi
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
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Eymery MC, McCarthy AA, Hausmann J. Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling. Life Sci Alliance 2023; 6:e202201595. [PMID: 36623871 PMCID: PMC9834664 DOI: 10.26508/lsa.202201595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/08/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 01/11/2023] Open
Abstract
Autotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine. LPA is an important signaling phospholipid that can bind to six G protein-coupled receptors (LPA1-6). The ATX-LPA signaling axis is a critical component in many physiological and pathophysiological conditions. Here, we describe a potent inhibition of Δ9-trans-tetrahydrocannabinol (THC), the main psychoactive compound of medicinal cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar apparent EC50 values. Furthermore, we decipher the binding interface of ATX to THC, and its derivative 9(R)-Δ6a,10a-THC (6a10aTHC), by X-ray crystallography. Cellular experiments confirm this inhibitory effect, revealing a significant reduction of internalized LPA1 in the presence of THC with simultaneous ATX and lysophosphatidylcholine stimulation. Our results establish a functional interaction of THC with autotaxin-LPA signaling and highlight novel aspects of medicinal cannabis therapy.
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Affiliation(s)
- Mathias C Eymery
- European Molecular Biology Laboratory, Grenoble, Grenoble, France
| | | | - Jens Hausmann
- European Molecular Biology Laboratory, Grenoble, Grenoble, France
- European Molecular Biology Laboratory, Chemical Biology Core Facility, Heidelberg, Germany
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Salgado-Polo F, Borza R, Matsoukas MT, Marsais F, Jagerschmidt C, Waeckel L, Moolenaar WH, Ford P, Heckmann B, Perrakis A. Autotaxin facilitates selective LPA receptor signaling. Cell Chem Biol 2023; 30:69-84.e14. [PMID: 36640760 DOI: 10.1016/j.chembiol.2022.12.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/24/2022] [Revised: 09/27/2022] [Accepted: 12/19/2022] [Indexed: 01/15/2023]
Abstract
Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA1-3) and P2Y (LPA4-6) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that the ATX "tunnel" is crucial for conferring key aspects of ATX/LPA signaling and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. The efficacy of the ATX/LPA signaling responses are abrogated more efficiently by tunnel-binding inhibitors, such as ziritaxestat (GLPG1690), compared with inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.
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Affiliation(s)
- Fernando Salgado-Polo
- Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
| | - Razvan Borza
- Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
| | | | - Florence Marsais
- Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France
| | | | - Ludovic Waeckel
- Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France
| | - Wouter H Moolenaar
- Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | - Paul Ford
- Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium
| | - Bertrand Heckmann
- Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France
| | - Anastassis Perrakis
- Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands.
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7
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Vít O, Petrák J. Autotaxin and Lysophosphatidic Acid Signalling: the Pleiotropic Regulatory Network in Cancer. Folia Biol (Praha) 2023; 69:149-162. [PMID: 38583176 DOI: 10.14712/fb2023069050149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 04/09/2024]
Abstract
Autotaxin, also known as ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2, is a secreted glycoprotein that plays multiple roles in human physiology and cancer pathology. This protein, by converting lysophosphatidylcholine into lysophosphatidic acid, initiates a complex signalling cascade with significant biological implications. The article outlines the autotaxin gene and protein structure, expression regulation and physiological functions, but focuses mainly on the role of autotaxin in cancer development and progression. Autotaxin and lysophosphatidic acid signalling influence several aspects of cancer, including cell proliferation, migration, metastasis, therapy resistance, and interactions with the immune system. The potential of autotaxin as a diagnostic biomarker and promising drug target is also examined.
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Affiliation(s)
- Ondřej Vít
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
| | - Jiří Petrák
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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Spencer SA, Suárez-Pozos E, Verdugo JS, Wang H, Afshari FS, Li G, Manam S, Yasuda D, Ortega A, Lister JA, Ishii S, Zhang Y, Fuss B. Lysophosphatidic acid signaling via LPA 6 : A negative modulator of developmental oligodendrocyte maturation. J Neurochem 2022; 163:478-499. [PMID: 36153691 PMCID: PMC9772207 DOI: 10.1111/jnc.15696] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/22/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 01/14/2023]
Abstract
The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G protein-coupled receptor LPA6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA6 and LPA6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA6 protein levels appear elevated in MS brain samples, thereby suggesting that LPA6 signaling may represent a potential new druggable pathway suitable to promote myelin repair in MS.
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Affiliation(s)
- Samantha A Spencer
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Edna Suárez-Pozos
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Jazmín Soto Verdugo
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Huiqun Wang
- Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, USA
| | - Fatemah S Afshari
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Guo Li
- Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, USA
| | - Susmita Manam
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Daisuke Yasuda
- Department of Immunology, Akita University Graduate School of Medicine, Akita, Japan
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - James A Lister
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Satoshi Ishii
- Department of Immunology, Akita University Graduate School of Medicine, Akita, Japan
| | - Yan Zhang
- Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, USA
| | - Babette Fuss
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Drosouni A, Panagopoulou M, Aidinis V, Chatzaki E. Autotaxin in Breast Cancer: Role, Epigenetic Regulation and Clinical Implications. Cancers (Basel) 2022; 14:5437. [PMID: 36358855 PMCID: PMC9658281 DOI: 10.3390/cancers14215437] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/15/2022] [Revised: 10/31/2022] [Accepted: 10/31/2022] [Indexed: 08/02/2023] Open
Abstract
Autotaxin (ATX), the protein product of Ectonucleotide Pyrophosphatase Phosphodiesterase 2 (ENPP2), is a secreted lysophospholipase D (lysoPLD) responsible for the extracellular production of lysophosphatidic acid (LPA). ATX-LPA pathway signaling participates in several normal biological functions, but it has also been connected to cancer progression, metastasis and inflammatory processes. Significant research has established a role in breast cancer and it has been suggested as a therapeutic target and/or a clinically relevant biomarker. Recently, ENPP2 methylation was described, revealing a potential for clinical exploitation in liquid biopsy. The current review aims to gather the latest findings about aberrant signaling through ATX-LPA in breast cancer and discusses the role of ENPP2 expression and epigenetic modification, giving insights with translational value.
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Affiliation(s)
- Andrianna Drosouni
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
| | - Vassilis Aidinis
- Institute of BioInnovation, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
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Structure and function of the Ecto-Nucleotide Pyrophosphatase-Phosphodiesterase (ENPP) family: tidying up diversity. J Biol Chem 2021; 298:101526. [PMID: 34958798 PMCID: PMC8808174 DOI: 10.1016/j.jbc.2021.101526] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/01/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 12/11/2022] Open
Abstract
Ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family members (ENPP1–7) have been implicated in key biological and pathophysiological processes, including nucleotide and phospholipid signaling, bone mineralization, fibrotic diseases, and tumor-associated immune cell infiltration. ENPPs are single-pass transmembrane ecto-enzymes, with notable exceptions of ENPP2 (Autotaxin) and ENNP6, which are secreted and glycosylphosphatidylinositol (GPI)-anchored, respectively. ENNP1 and ENNP2 are the best characterized and functionally the most interesting members. Here, we review the structural features of ENPP1–7 to understand how they evolved to accommodate specific substrates and mediate different biological activities. ENPPs are defined by a conserved phosphodiesterase (PDE) domain. In ENPP1–3, the PDE domain is flanked by two N-terminal somatomedin B-like domains and a C-terminal inactive nuclease domain that confers structural stability, whereas ENPP4–7 only possess the PDE domain. Structural differences in the substrate-binding site endow each protein with unique characteristics. Thus, ENPP1, ENPP3, ENPP4, and ENPP5 hydrolyze nucleotides, whereas ENPP2, ENPP6, and ENNP7 evolved as phospholipases through adaptions in the catalytic domain. These adaptations explain the different biological and pathophysiological functions of individual members. Understanding the ENPP members as a whole advances our insights into common mechanisms, highlights their functional diversity, and helps to explore new biological roles.
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Jia Y, Li Y, Xu XD, Tian Y, Shang H. Design and Development of Autotaxin Inhibitors. Pharmaceuticals (Basel) 2021; 14:ph14111203. [PMID: 34832985 PMCID: PMC8622848 DOI: 10.3390/ph14111203] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/28/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and cytokine production, through six G protein-coupled receptors (LPA1-6). This signaling pathway is associated with metabolic and inflammatory disorder, and inhibiting this pathway has a positive effect on the treatment of related diseases, while ATX, as an important role in the production of LPA, has been shown to be associated with the occurrence and metastasis of tumors, fibrosis and cardiovascular diseases. From mimics of ATX natural lipid substrates to the rational design of small molecule inhibitors, ATX inhibitors have made rapid progress in structural diversity and design over the past 20 years, and three drugs, GLPG1690, BBT-877, and BLD-0409, have entered clinical trials. In this paper, we will review the structure of ATX inhibitors from the perspective of the transformation of design ideas, discuss the advantages and disadvantages of each inhibitor type, and put forward prospects for the development of ATX inhibitors in the future.
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Affiliation(s)
| | | | | | - Yu Tian
- Correspondence: (Y.T.); (H.S.)
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12
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Matas-Rico E, Frijlink E, van der Haar Àvila I, Menegakis A, van Zon M, Morris AJ, Koster J, Salgado-Polo F, de Kivit S, Lança T, Mazzocca A, Johnson Z, Haanen J, Schumacher TN, Perrakis A, Verbrugge I, van den Berg JH, Borst J, Moolenaar WH. Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8 + T cells. Cell Rep 2021; 37:110013. [PMID: 34788605 PMCID: PMC8761359 DOI: 10.1016/j.celrep.2021.110013] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/23/2020] [Revised: 10/07/2021] [Accepted: 10/26/2021] [Indexed: 01/22/2023] Open
Abstract
Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1–6. ATX/LPA promotes tumor cell migration and metastasis via LPAR1 and T cell motility via LPAR2, yet its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) and circulating CD8+ T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T cell repulsion predominantly involves Gα12/13-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor regression. Moreover, single-cell data from melanoma tumors are consistent with intratumoral ATX acting as a T cell repellent. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities. Through LPA production, ATX modulates the tumor microenvironment in autocrine-paracrine manners. Matas-Rico et al. show that ATX/LPA is chemorepulsive for T cells with a dominant inhibitory role for Gα12/13-coupled LPAR6. Upon anticancer vaccination, tumor-intrinsic ATX suppresses the infiltration of CD8+ T cells without affecting their cytotoxic quality.
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Affiliation(s)
- Elisa Matas-Rico
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Elselien Frijlink
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Irene van der Haar Àvila
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Apostolos Menegakis
- Oncode Institute, Utrecht, the Netherlands; Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Maaike van Zon
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Andrew J Morris
- Division of Cardiovascular Medicine, Gill Heart Institute and Lexington Veterans Affairs Medical Center, University of Kentucky, Lexington, KY, USA
| | - Jan Koster
- Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, Amsterdam, the Netherlands
| | - Fernando Salgado-Polo
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Sander de Kivit
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Telma Lança
- Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Zoë Johnson
- iOnctura SA, Campus Biotech Innovation Park, Geneva, Switzerland
| | - John Haanen
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Ton N Schumacher
- Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Anastassis Perrakis
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Inge Verbrugge
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Joost H van den Berg
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jannie Borst
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
| | - Wouter H Moolenaar
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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Zhang X, Li M, Yin N, Zhang J. The Expression Regulation and Biological Function of Autotaxin. Cells 2021; 10:cells10040939. [PMID: 33921676 PMCID: PMC8073485 DOI: 10.3390/cells10040939] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/24/2021] [Revised: 04/15/2021] [Accepted: 04/15/2021] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX) is a secreted glycoprotein and functions as a key enzyme to produce extracellular lysophosphatidic acid (LPA). LPA interacts with at least six G protein-coupled receptors, LPAR1-6, on the cell membrane to activate various signal transduction pathways through distinct G proteins, such as Gi/0, G12/13, Gq/11, and Gs. The ATX-LPA axis plays an important role in physiological and pathological processes, including embryogenesis, obesity, and inflammation. ATX is one of the top 40 most unregulated genes in metastatic cancer, and the ATX-LPA axis is involved in the development of different types of cancers, such as colorectal cancer, ovarian cancer, breast cancer, and glioblastoma. ATX expression is under multifaceted controls at the transcription, post-transcription, and secretion levels. ATX and LPA in the tumor microenvironment not only promote cell proliferation, migration, and survival, but also increase the expression of inflammation-related circuits, which results in poor outcomes for patients with cancer. Currently, ATX is regarded as a potential cancer therapeutic target, and an increasing number of ATX inhibitors have been developed. In this review, we focus on the mechanism of ATX expression regulation and the functions of ATX in cancer development.
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Affiliation(s)
| | | | | | - Junjie Zhang
- Correspondence: ; Tel.: +86-10-58802137; Fax: +86-10-58807720
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Abstract
INTRODUCTION The ATX-LPA axis is an attractive target for therapeutic intervention in a variety of diseases, such as tumor metastasis, fibrosis, pruritus, multiple sclerosis, inflammation, autoimmune conditions, metabolic syndrome, and so on. Accordingly, considerable efforts have been devoted to the development of new chemical entities capable of modulating the ATX-LPA axis. AREAS COVERED This review aims to provide an overview of novel ATX inhibitors reported in patents from September 2016 to August 2020, discussing their structural characteristics and inhibitory potency in vitro and in vivo. EXPERT OPINION In the past four years, the classification of ATX inhibitors based on binding modes has brought great benefits to the discovery of more efficacious inhibitors. In addition to GLPG1690 currently in phase III clinical studies for IPF, BBT-877, and BLD-0409 as potent ATX inhibitors have been enrolled in phase I clinical evaluation; meanwhile, many effective molecules were also reported successively. However, most emerging ATX inhibitors in the last four years are closely analogs of previous entities, such as GLPG1690 and PF-8380, which translate into the urgently identification of ATX inhibitors with diverse structural features and promising properties in the near future.
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Affiliation(s)
- Zehui Tan
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Hongrui Lei
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Ming Guo
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Yuxiang Chen
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Xin Zhai
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
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15
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Roles for lysophosphatidic acid signaling in vascular development and disease. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158734. [PMID: 32376340 DOI: 10.1016/j.bbalip.2020.158734] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/03/2020] [Revised: 04/27/2020] [Accepted: 04/29/2020] [Indexed: 01/28/2023]
Abstract
The bioactive lipid lysophosphatidic acid (LPA) is emerging as an important mediator of inflammation in cardiovascular diseases. Produced in large part by the secreted lysophospholipase D autotaxin (ATX), LPA acts on a series of G protein-coupled receptors and may have action on atypical receptors such as RAGE to exert potent effects on vascular cells, including the promotion of foam cell formation and phenotypic modulation of smooth muscle cells. The signaling effects of LPA can be terminated by integral membrane lipid phosphate phosphatases (LPP) that hydrolyze the lipid to receptor inactive products. Human genetic variants in PLPP3, that predict lower levels of LPP3, associate with risk for premature coronary artery disease, and reductions of LPP3 expression in mice promote the development of experimental atherosclerosis and enhance inflammation in the atherosclerotic lesions. Recent evidence also supports a role for ATX, and potentially LPP3, in calcific aortic stenosis. In summary, LPA may be a relevant inflammatory mediator in atherosclerotic cardiovascular disease and heightened LPA signaling may explain the cardiovascular disease risk effect of PLPP3 variants.
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Tang X, Benesch MGK, Brindley DN. Role of the autotaxin-lysophosphatidate axis in the development of resistance to cancer therapy. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158716. [PMID: 32305571 DOI: 10.1016/j.bbalip.2020.158716] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/08/2020] [Revised: 03/31/2020] [Accepted: 04/09/2020] [Indexed: 12/17/2022]
Abstract
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidate (LPA), which signals through six G-protein coupled receptors (GPCRs). Signaling through LPA is terminated by its degradation by a family of three lipid phosphate phosphatases (LPPs). LPP1 also attenuates signaling downstream of the activation of LPA receptors and some other GPCRs. The ATX-LPA axis mediates a plethora of activities such as cell proliferation, survival, migration, angiogenesis and inflammation, which perform an important role in facilitating wound healing. This wound healing response is hijacked by cancers where there is decreased expression of LPP1 and LPP3 and increased expression of ATX. This maladaptive regulation of LPA signaling also causes chronic inflammation, which has been recognized as one of the hallmarks in cancer. The increased LPA signaling promotes cell survival and migration and attenuates apoptosis, which stimulates tumor growth and metastasis. The wound healing functions of increased LPA signaling also protect cancer cells from effects of chemotherapy and radiotherapy. In this review, we will summarize knowledge of the ATX-LPA axis and its role in the development of resistance to chemotherapy and radiotherapy. We will also offer insights for developing strategies of targeting ATX-LPA axis as a novel part of cancer treatment. This article is part of a Special Issue entitled Lysophospholipids and their receptors: New data and new insights into their function edited by Susan Smyth, Viswanathan Natarajan and Colleen McMullen.
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Affiliation(s)
- Xiaoyun Tang
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada
| | - Matthew G K Benesch
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada; Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador A1B 3V6, Canada
| | - David N Brindley
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada.
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He L, Xu H, Ye F, Yu H, Lu Y, Yin H, Zhao X, Zhu Q, Wang Y. Expression Pattern of Sulf1 and Sulf2 in Chicken Tissues and Characterization of Their Expression During Different Periods in Skeletal Muscle Satellite Cells. BRAZILIAN JOURNAL OF POULTRY SCIENCE 2020. [DOI: 10.1590/1806-9061-2019-1165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022]
Affiliation(s)
- L He
- Sichuan Agricultural University, China
| | - H Xu
- Sichuan Agricultural University, China
| | - F Ye
- Sichuan Agricultural University, China
| | - H Yu
- Sichuan Agricultural University, China
| | - Y Lu
- Sichuan Agricultural University, China
| | - H Yin
- Sichuan Agricultural University, China
| | - X Zhao
- Sichuan Agricultural University, China
| | - Q Zhu
- Sichuan Agricultural University, China
| | - Y Wang
- Sichuan Agricultural University, China
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18
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Peyruchaud O, Saier L, Leblanc R. Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface. Cancers (Basel) 2019; 12:cancers12010105. [PMID: 31906151 PMCID: PMC7016970 DOI: 10.3390/cancers12010105] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2019] [Revised: 12/19/2019] [Accepted: 12/29/2019] [Indexed: 12/18/2022] Open
Abstract
Autotaxin (ATX) is an exoenzyme which, due to its unique lysophospholipase D activity, is responsible for the synthesis of lysophosphatidic acid (LPA). ATX activity is responsible for the concentration of LPA in the blood. ATX expression is increased in various types of cancers, including breast cancer, where it promotes metastasis. The expression of ATX is also remarkably increased under inflammatory conditions, particularly in the osteoarticular compartment, where it controls bone erosion. Biological actions of ATX are mediated by LPA. However, the phosphate head group of LPA is highly sensitive to degradation by the action of lipid phosphate phosphatases, resulting in LPA inactivation. This suggests that for efficient action, LPA requires protection, which is potentially achieved through docking to a carrier protein. Interestingly, recent reports suggest that ATX might act as a docking molecule for LPA and also support the concept that binding of ATX to the cell surface through its interaction with adhesive molecules (integrins, heparan sulfate proteoglycans) could facilitate a rapid route of delivering active LPA to its cell surface receptors. This new mechanism offers a new vision of how ATX/LPA works in cancer metastasis and inflammatory bone diseases, paving the way for new therapeutic developments.
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Affiliation(s)
- Olivier Peyruchaud
- INSERM, Unit 1033, Université Claude Bernard Lyon 1, 69372 Lyon, France;
- Correspondence: ; Tel.: +3-34-78-77-86-72
| | - Lou Saier
- INSERM, Unit 1033, Université Claude Bernard Lyon 1, 69372 Lyon, France;
| | - Raphaël Leblanc
- Centre de Recherche en Cancérologie de Marseille, Institut Poli-Calmettes, INSERM, Unit 1068, University Aix/Marseille, 13009 Marseille, France;
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19
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The Structural Binding Mode of the Four Autotaxin Inhibitor Types that Differentially Affect Catalytic and Non-Catalytic Functions. Cancers (Basel) 2019; 11:cancers11101577. [PMID: 31623219 PMCID: PMC6826961 DOI: 10.3390/cancers11101577] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/10/2019] [Revised: 09/27/2019] [Accepted: 10/08/2019] [Indexed: 12/20/2022] Open
Abstract
Autotaxin (ATX) is a secreted lysophospholipase D, catalysing the conversion of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA acts through two families of G protein-coupled receptors (GPCRs) controlling key cellular responses, and it is implicated in many physiological processes and pathologies. ATX, therefore, has been established as an important drug target in the pharmaceutical industry. Structural and biochemical studies of ATX have shown that it has a bimetallic nucleophilic catalytic site, a substrate-binding (orthosteric) hydrophobic pocket that accommodates the lipid alkyl chain, and an allosteric tunnel that can accommodate various steroids and LPA. In this review, first, we revisit what is known about ATX-mediated catalysis, crucially in light of allosteric regulation. Then, we present the known ATX catalysis-independent functions, including binding to cell surface integrins and proteoglycans. Next, we analyse all crystal structures of ATX bound to inhibitors and present them based on the four inhibitor types that are established based on the binding to the orthosteric and/or the allosteric site. Finally, in light of these data we discuss how mechanistic differences might differentially modulate the activity of the ATX-LPA signalling axis, and clinical applications including cancer.
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20
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Hypoxia Downregulates LPP3 and Promotes the Spatial Segregation of ATX and LPP1 During Cancer Cell Invasion. Cancers (Basel) 2019; 11:cancers11091403. [PMID: 31546971 PMCID: PMC6769543 DOI: 10.3390/cancers11091403] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/09/2019] [Revised: 09/07/2019] [Accepted: 09/12/2019] [Indexed: 12/16/2022] Open
Abstract
Hypoxia is a common characteristic of advanced solid tumors and a potent driver of tumor invasion and metastasis. Recent evidence suggests the involvement of autotaxin (ATX) and lysophosphatidic acid receptors (LPARs) in cancer cell invasion promoted by the hypoxic tumor microenvironment; however, the transcriptional and/or spatiotemporal control of this process remain unexplored. Herein, we investigated whether hypoxia promotes cell invasion by affecting the main enzymes involved in its production (ATX) and degradation (lipid phosphate phosphatases, LPP1 and LPP3). We report that hypoxia not only modulates the expression levels of lysophosphatidic acid (LPA) regulatory enzymes but also induces their significant spatial segregation in a variety of cancers. While LPP3 expression was downregulated by hypoxia, ATX and LPP1 were asymmetrically redistributed to the leading edge and to the trailing edge, respectively. This was associated with the opposing roles of ATX and LPPs in cell invasion. The regulated expression and compartmentalization of these enzymes of opposing function can provide an effective way to control the generation of an LPA gradient that drives cellular invasion and migration in the hypoxic zones of tumors.
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21
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Lysophosphatidic Acid and Autotaxin-associated Effects on the Initiation and Progression of Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11070958. [PMID: 31323936 PMCID: PMC6678549 DOI: 10.3390/cancers11070958] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/10/2019] [Revised: 07/04/2019] [Accepted: 07/08/2019] [Indexed: 02/07/2023] Open
Abstract
The intestinal epithelium interacts dynamically with the immune system to maintain its barrier function to protect the host, while performing the physiological roles in absorption of nutrients, electrolytes, water and minerals. The importance of lysophosphatidic acid (LPA) and its receptors in the gut has been progressively appreciated. LPA signaling modulates cell proliferation, invasion, adhesion, angiogenesis, and survival that can promote cancer growth and metastasis. These effects are equally important for the maintenance of the epithelial barrier in the gut, which forms the first line of defense against the milieu of potentially pathogenic stimuli. This review focuses on the LPA-mediated signaling that potentially contributes to inflammation and tumor formation in the gastrointestinal tract.
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22
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Lin S, Haque A, Raeman R, Guo L, He P, Denning TL, El-Rayes B, Moolenaar WH, Yun CC. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon. FASEB J 2019; 33:3623-3635. [PMID: 30481488 PMCID: PMC6404565 DOI: 10.1096/fj.201801415rr] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/09/2018] [Accepted: 10/22/2018] [Indexed: 12/13/2022]
Abstract
Autotaxin (ATX or ENPP2) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a pleiotropic lipid mediator acting on specific GPCRs. ATX and LPA have been implicated in key (patho)physiologic processes, including embryonic development, lymphocyte homing, inflammation, and cancer progression. Using LPA receptor knockout mice, we previously uncovered a role for LPA signaling in promoting colitis and colorectal cancer. Here, we examined the role of ATX in experimental colitis through inducible deletion of Enpp2 in adult mice. ATX expression was increased upon induction of colitis, whereas ATX deletion reduced the severity of inflammation in both acute and chronic colitis, accompanied by transient weight loss. ATX expression in lymphocytes was strongly reduced in Rag1-/- and μMT mice, suggesting B cells as a major ATX-producing source, which was validated by immunofluorescence and biochemical analyses. ATX secretion by B cells from control, but not Enpp2 knockout, mice led to ERK activation in colorectal cancer cells and promoted T cell migration. We conclude that ATX deletion suppresses experimental colitis and that B cells are a major source of ATX in the colon. Our study suggests that pharmacological inhibition of ATX could be a therapeutic strategy in colitis.-Lin, S., Haque, A., Raeman, R., Guo, L., He, P., Denning, T. L., El-Rayes, B., Moolenaar, W. H., Yun, C. C. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon.
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Affiliation(s)
- Songbai Lin
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Abedul Haque
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Reben Raeman
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Leilei Guo
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Peijian He
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Timothy L. Denning
- Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA
| | - Bassel El-Rayes
- Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA; and
| | - Wouter H. Moolenaar
- Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - C. Chris Yun
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA; and
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23
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Matralis AN, Afantitis A, Aidinis V. Development and therapeutic potential of autotaxin small molecule inhibitors: From bench to advanced clinical trials. Med Res Rev 2018; 39:976-1013. [PMID: 30462853 DOI: 10.1002/med.21551] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/06/2018] [Revised: 09/21/2018] [Accepted: 10/19/2018] [Indexed: 12/11/2022]
Abstract
Several years after its isolation from melanoma cells, an increasing body of experimental evidence has established the involvement of Autotaxin (ATX) in the pathogenesis of several diseases. ATX, an extracellular enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA), is overexpressed in a variety of human metastatic cancers and is strongly implicated in chronic inflammation and liver toxicity, fibrotic diseases, and thrombosis. Accordingly, the ATX-LPA signaling pathway is considered a tractable target for therapeutic intervention substantiated by the multitude of research campaigns that have been successful in identifying ATX inhibitors by both academia and industry. Furthermore, from a therapeutic standpoint, the entry and the so far promising results of the first ATX inhibitor in advanced clinical trials against idiopathic pulmonary fibrosis (IPF) lends support to the viability of this approach, bringing it to the forefront of drug discovery efforts. The present review article aims to provide a comprehensive overview of the most important series of ATX inhibitors developed so far. Special weight is lent to the design, structure activity relationship and mode of binding studies carried out, leading to the identification of advanced leads. The most significant in vitro and in vivo pharmacological results of these advanced leads are also summarized. Lastly, the development of the first ATX inhibitor entered in clinical trials accompanied by its phase 1 and 2a clinical trial data is disclosed.
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Affiliation(s)
- Alexios N Matralis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece
| | - Antreas Afantitis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece.,NovaMechanics Ltd Cheminformatics Company, Nicosia, Cyprus
| | - Vassilis Aidinis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece
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24
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He P, Haque A, Lin S, Cominelli F, Yun CC. Inhibition of autotaxin alleviates inflammation and increases the expression of sodium-dependent glucose cotransporter 1 and Na +/H + exchanger 3 in SAMP1/Fc mice. Am J Physiol Gastrointest Liver Physiol 2018; 315:G762-G771. [PMID: 30118349 PMCID: PMC6293258 DOI: 10.1152/ajpgi.00215.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/31/2023]
Abstract
Crohn's disease (CD) is a chronic, relapsing, inflammatory disease that is often associated with malnutrition because of inflammation in the small intestine. Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidic acid. Increasing evidence suggests that ATX is upregulated during inflammation, and inhibition of ATX has been effective in attenuating chronic inflammatory conditions, such as arthritis and pulmonary fibrosis. This study aims to determine whether inhibition of ATX alleviates CD-associated inflammation and malnutrition by using SAMP1/Fc mice, a model of CD-like ileitis. SAMP1/Fc mice were treated the ATX inhibitor PF-8380 for 4 wk. Inhibition of ATX led to increased weight gain in SAMP1/Fc mice, decreased T helper 2 cytokine expression, including IL-4, IL-5, and IL-13, and attenuated immune cell migration. SAMP1/Fc mice have low expression of Na+-dependent glucose transporter 1 (SGLT1), suggesting impaired nutrient absorption associated with ileitis. PF-8380 treatment significantly enhanced SGLT1 expression in SAMP1/Fc mice, which could reflect the increased weight changes. However, IL-4 or IL-13 did not alter SGLT1 expression in Caco-2 cells, ruling out their direct effects on SGLT1 expression. Immunofluorescence analysis showed that the expression of sucrase-isomaltase, a marker for intestinal epithelial cell (IEC) differentiation, was decreased in inflamed regions of SAMP1/Fc mice, which was partially restored by PF-8380. Moreover, expression of Na+/H+ exchanger 3 was also improved by PF-8380, suggesting that suppression of inflammation by PF-8380 enhanced IEC differentiation. Our study therefore suggests that ATX is a potential target for treating intestinal inflammation and restoration of the absorptive function of the intestine. NEW & NOTEWORTHY This study is the first, to our knowledge, to determine whether autotoxin (ATX) inhibition improves inflammation and body weights in SAMP1/Fc mice, a mouse model of ileitis. ATX inhibition increased body weights of SAMP1/Fc mice and increased Na+-dependent glucose transporter 1 (SGLT1) expression. Increased SGLT1 expression in the inflamed regions was not a direct effect of cytokines but an indirect effect of increased epithelial cell differentiation upon ATX inhibition.
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Affiliation(s)
- Peijian He
- 1Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia,2Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - Abedul Haque
- 1Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia,2Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - Songbai Lin
- 1Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia,2Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - Fabio Cominelli
- 3Department of Medicine, Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio
| | - C. Chris Yun
- 1Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia,2Atlanta Veterans Affairs Medical Center, Decatur, Georgia,4Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
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25
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Yang F, Chen GX. Production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis. World J Gastroenterol 2018; 24:4132-4151. [PMID: 30271079 PMCID: PMC6158478 DOI: 10.3748/wjg.v24.i36.4132] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/24/2018] [Revised: 04/24/2018] [Accepted: 05/05/2018] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in sub-millimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin (ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.
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Affiliation(s)
- Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, United States
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26
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Leblanc R, Sahay D, Houssin A, Machuca-Gayet I, Peyruchaud O. Autotaxin-β interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis. Oncotarget 2018; 9:33170-33185. [PMID: 30237860 PMCID: PMC6145688 DOI: 10.18632/oncotarget.26039] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/02/2018] [Accepted: 08/10/2018] [Indexed: 01/16/2023] Open
Abstract
Autotaxin (ATX) promotes cancer cell metastasis through the production of lysophosphatidic acid (LPA). ATX binds to αvβ3 integrins controlling metastasis of breast cancer cells. We screened a series of cancer cell lines derived from diverse human and mouse solid tumors for the capacity of binding to ATX and found only a modest correlation with their level of αvβ3 integrin expression. These results strongly suggested the existence of another cell surface ATX-interacting factor. Indeed, ATXα has been shown to bind heparan-sulfate chains because of its unique polybasic insertion sequence, although the biological significance is unknown. We demonstrated here, that among all cell surface heparan-sulfate proteoglycans, syndecan-4 (SDC4) was essential for cancer cell interaction with ATXβ but was restrained by heparan-sulfate chains. In addition, exogenous ATXβ-induced MG63 osteosarcoma cell proliferation required physical interaction of ATXβ with the cell surface via an SDC4-dependent mechanism. In a preclininal mouse model, targeting SDC4 on 4T1 mouse breast cancer cells inhibited early bone metastasis formation. Furthermore, SDC4-prometastatic activity was totally abolished in absence of ATX expression. In conclusion our results determined that ATX and SDC4 are engaged in a reciprocal collaboration for cancer cell metastasis providing the rational for the development of novel anti-metastasis therapies.
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Affiliation(s)
- Raphael Leblanc
- Centre de Recherche en Cancérologie de Marseille, Marseille, France.,Institut Poli-Calmettes, Marseille, France.,INSERM, Unit 1068, Marseille, France.,University Aix-Marseille, Marseille, France
| | - Debashish Sahay
- Department of Medicine, Colombia University Medical Center, New York City, NY, USA
| | - Audrey Houssin
- INSERM, Unit 1033, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Irma Machuca-Gayet
- INSERM, Unit 1033, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Olivier Peyruchaud
- INSERM, Unit 1033, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
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27
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Salgado-Polo F, Fish A, Matsoukas MT, Heidebrecht T, Keune WJ, Perrakis A. Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency. J Biol Chem 2018; 293:14312-14327. [PMID: 30026231 DOI: 10.1074/jbc.ra118.004450] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/13/2018] [Revised: 07/13/2018] [Indexed: 12/18/2022] Open
Abstract
Autotaxin (ATX) is a secreted glycoprotein and the only member of the ectonucleotide pyrophosphatase/phosphodiesterase family that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key responses, such as cell migration, proliferation, and survival, implicating ATX-LPA signaling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, called the "pocket" and the "tunnel," respectively. However, the mechanisms in allosteric modulation of ATX's activity as a lysophospholipase D are unclear. Here, using the physiological LPC substrate, a new fluorescent substrate, and diverse ATX inhibitors, we revisited the kinetics and allosteric regulation of the ATX catalytic cycle, dissecting the different steps and pathways leading to LPC hydrolysis. We found that ATX activity is stimulated by LPA and that LPA activates ATX lysophospholipase D activity by binding to the ATX tunnel. A consolidation of all experimental kinetics data yielded a comprehensive catalytic model supported by molecular modeling simulations and suggested a positive feedback mechanism that is regulated by the abundance of the LPA products activating hydrolysis of different LPC species. Our results complement and extend the current understanding of ATX hydrolysis in light of the allosteric regulation by ATX-produced LPA species and have implications for the design and application of both orthosteric and allosteric ATX inhibitors.
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Affiliation(s)
- Fernando Salgado-Polo
- From the Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands and
| | - Alex Fish
- From the Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands and
| | - Minos-Timotheos Matsoukas
- From the Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands and.,the Department of Pharmacy, University of Patras, 26504 Patras, Greece
| | - Tatjana Heidebrecht
- From the Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands and
| | - Willem-Jan Keune
- From the Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands and
| | - Anastassis Perrakis
- From the Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands and
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28
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Ninou I, Magkrioti C, Aidinis V. Autotaxin in Pathophysiology and Pulmonary Fibrosis. Front Med (Lausanne) 2018; 5:180. [PMID: 29951481 PMCID: PMC6008954 DOI: 10.3389/fmed.2018.00180] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/31/2018] [Accepted: 05/25/2018] [Indexed: 12/17/2022] Open
Abstract
Lysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2), or as more widely known Autotaxin (ATX), a secreted lysophospholipase D (lysoPLD) largely responsible for extracellular lysophosphatidic acid (LPA) production. In turn, LPA is a bioactive phospholipid autacoid, forming locally upon increased ATX levels and acting also locally through its receptors, likely guided by ATX's structural conformation and cell surface associations. Increased ATX activity levels have been detected in many inflammatory and fibroproliferative conditions, while genetic and pharmacologic studies have confirmed a pleiotropic participation of ATX/LPA in different processes and disorders. In pulmonary fibrosis, ATX levels rise in the broncheoalveolar fluid (BALF) and stimulate LPA production. LPA engagement of its receptors activate multiple G-protein mediated signal transduction pathways leading to different responses from pulmonary cells including the production of pro-inflammatory signals from stressed epithelial cells, the modulation of endothelial physiology, the activation of TGF signaling and the stimulation of fibroblast accumulation. Genetic or pharmacologic targeting of the ATX/LPA axis attenuated disease development in animal models, thus providing the proof of principle for therapeutic interventions.
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Affiliation(s)
- Ioanna Ninou
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Christiana Magkrioti
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Vassilis Aidinis
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
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29
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D'Souza K, Paramel GV, Kienesberger PC. Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance. Nutrients 2018; 10:nu10040399. [PMID: 29570618 PMCID: PMC5946184 DOI: 10.3390/nu10040399] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/31/2018] [Revised: 03/13/2018] [Accepted: 03/20/2018] [Indexed: 12/21/2022] Open
Abstract
Although simple in structure, lysophosphatidic acid (LPA) is a potent bioactive lipid that profoundly influences cellular signaling and function upon binding to G protein-coupled receptors (LPA1-6). The majority of circulating LPA is produced by the secreted enzyme autotaxin (ATX). Alterations in LPA signaling, in conjunction with changes in autotaxin (ATX) expression and activity, have been implicated in metabolic and inflammatory disorders including obesity, insulin resistance, and cardiovascular disease. This review summarizes our current understanding of the sources and metabolism of LPA with focus on the influence of diet on circulating LPA. Furthermore, we explore how the ATX-LPA pathway impacts obesity and obesity-associated disorders, including impaired glucose homeostasis, insulin resistance, and cardiovascular disease.
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Affiliation(s)
- Kenneth D'Souza
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5 Canada.
| | - Geena V Paramel
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5 Canada.
| | - Petra C Kienesberger
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5 Canada.
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30
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Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling. Nat Commun 2016; 7:11248. [PMID: 27075612 PMCID: PMC4834639 DOI: 10.1038/ncomms11248] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/19/2015] [Accepted: 03/04/2016] [Indexed: 12/12/2022] Open
Abstract
Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs. Autotaxin generates the bioactive lipid lysophosphatidic acid to regulate diverse biological processes. Here, the authors identify a role for bile salts as direct allosteric inhibitors of autotaxin activity, suggesting that steroids may function as regulators of lysophosphatidic acid signalling.
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31
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Federico L, Jeong KJ, Vellano CP, Mills GB. Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression. J Lipid Res 2016; 57:25-35. [PMID: 25977291 PMCID: PMC4689343 DOI: 10.1194/jlr.r060020] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/15/2015] [Revised: 05/07/2015] [Indexed: 12/18/2022] Open
Abstract
The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, inflammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers.
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Affiliation(s)
- Lorenzo Federico
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Kang Jin Jeong
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Christopher P Vellano
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Gordon B Mills
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
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32
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Benesch MGK, Tang X, Dewald J, Dong WF, Mackey JR, Hemmings DG, McMullen TPW, Brindley DN. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression. FASEB J 2015; 29:3990-4000. [DOI: 10.1096/fj.15-274480] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/09/2015] [Accepted: 05/26/2015] [Indexed: 02/06/2023]
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33
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Balogh A, Shimizu Y, Lee SC, Norman DD, Gangwar R, Bavaria M, Moon C, Shukla P, Rao R, Ray R, Naren AP, Banerjee S, Banerje S, Miller DD, Balazs L, Pelus L, Tigyi G. The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair. Cell Signal 2015; 27:1751-62. [PMID: 26027517 DOI: 10.1016/j.cellsig.2015.05.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/05/2015] [Accepted: 05/15/2015] [Indexed: 12/24/2022]
Abstract
In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA2 GPCR axis. In IEC-6 crypt cells and jejunum enteroids quantitative RT-PCR showed a time- and dose-dependent upregulation of lpa2 in response to γ-irradiation that was abolished by mutation of the NF-κB site in the lpa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that lpa2 is a DNA damage response gene upregulated by ATM via NF-κB. The resolution kinetics of the DNA damage marker γ-H2AX in LPA-treated IEC-6 cells exposed to γ-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of γ-H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of γ-H2AX decreased rapidly, whereas in Vector MEF were high and remained sustained. Inhibition of ERK1&2 or PI3K/AKT signaling axis by pertussis toxin or the C311A/C314A/L351A mutation in the C-terminus of LPA2 abrogated the effect of LPA on DNA repair. LPA2 transcripts in Lin(-)Sca-1(+)c-Kit(+) enriched for bone marrow stem cells were 27- and 5-fold higher than in common myeloid or lymphoid progenitors, respectively. Furthermore, after irradiation higher residual γ-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that γ-irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNFα. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair.
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Affiliation(s)
- Andrea Balogh
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Yoshibumi Shimizu
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Sue Chin Lee
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Derek D Norman
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Ruchika Gangwar
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Mitul Bavaria
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - ChangSuk Moon
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Pradeep Shukla
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Radakrishna Rao
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Ramesh Ray
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Anjaparavanda P Naren
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | | | - Souvik Banerje
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Duane D Miller
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Louisa Balazs
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA
| | - Louis Pelus
- Department of Microbiology & Immunology, Indiana University School of Medicine, 950 West Walnut Street, R2-302, Indianapolis, IN 46202, USA
| | - Gabor Tigyi
- Department of Physiology, University of Tennessee Health Sciences Center Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
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34
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Barbayianni E, Kaffe E, Aidinis V, Kokotos G. Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer. Prog Lipid Res 2015; 58:76-96. [DOI: 10.1016/j.plipres.2015.02.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/03/2014] [Revised: 01/20/2015] [Accepted: 02/12/2015] [Indexed: 02/07/2023]
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35
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Katakai T, Kondo N, Ueda Y, Kinashi T. Autotaxin produced by stromal cells promotes LFA-1-independent and Rho-dependent interstitial T cell motility in the lymph node paracortex. THE JOURNAL OF IMMUNOLOGY 2014; 193:617-26. [PMID: 24935929 DOI: 10.4049/jimmunol.1400565] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 11/19/2022]
Abstract
T cells exhibit high-speed migration within the paracortical T zone of lymph nodes (LNs) as they scan cognate Ags displayed by dendritic cells in the tissue microenvironment supported by the network of stromal cells. Although intranodal T cell migration is controlled in part by chemokines and LFA-1/ICAM-1, the mechanisms underlying their migratory activity independent of these factors remain to be elucidated. In this study, we show that LN stromal cells constitutively express autotaxin (ATX), an ectoenzyme that is important for the generation of lysophosphatidic acid (LPA). Importantly, CCL21(+) stromal cells in the T zone produced and immobilized ATX on their cell surface. Two-photon imaging using LN tissue slices revealed that pharmacological inhibition of ATX or LPA receptors significantly reduced T cell migration, and this was further exacerbated by blockage of Gαi signaling or LFA-1. Therefore, T cell motility mediated by the ATX-LPA axis was independent of Gαi and LFA-1. LPA induced slow intermittent movement of T cells in vitro in a LFA-1-independent manner and enhanced CCL21-induced migration. Moreover, LPA and CCL21 cooperatively augmented RhoA activity in T cells, which was necessary for efficient intranodal T cell migration via the downstream ROCK-myosin II pathway. Taken together, T zone stromal cells control optimal migratory behavior of T cells via multiple signaling cues mediated by chemokines and ATX/LPA.
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Affiliation(s)
- Tomoya Katakai
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Naoyuki Kondo
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Yoshihiro Ueda
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Tatsuo Kinashi
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
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36
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Potentials of the Circulating Pruritogenic Mediator Lysophosphatidic Acid in Development of Allergic Skin Inflammation in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:1593-603. [DOI: 10.1016/j.ajpath.2014.01.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 09/30/2013] [Revised: 01/05/2014] [Accepted: 01/16/2014] [Indexed: 01/03/2023]
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37
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Knowlden S, Georas SN. The autotaxin-LPA axis emerges as a novel regulator of lymphocyte homing and inflammation. THE JOURNAL OF IMMUNOLOGY 2014; 192:851-7. [PMID: 24443508 DOI: 10.4049/jimmunol.1302831] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022]
Abstract
Lysophosphatidic acid (LPA) is a pleiotropic lipid molecule with potent effects on cell growth and motility. Major progress has been made in recent years in deciphering the mechanisms of LPA generation and how it acts on target cells. Most research has been conducted in other disciplines, but emerging data indicate that LPA has an important role to play in immunity. A key discovery was that autotaxin (ATX), an enzyme previously implicated in cancer cell motility, generates extracellular LPA from the precursor lysophosphatidylcholine. Steady-state ATX is expressed by only a few tissues, including high endothelial venules in lymph nodes, but inflammatory signals can upregulate ATX expression in different tissues. In this article, we review current thinking about the ATX/LPA axis in lymphocyte homing, as well as in models of allergic airway inflammation and asthma. New insights into the role of LPA in regulating immune responses should be forthcoming in the near future.
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Affiliation(s)
- Sara Knowlden
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642
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38
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Benesch MGK, Tang X, Maeda T, Ohhata A, Zhao YY, Kok BPC, Dewald J, Hitt M, Curtis JM, McMullen TPW, Brindley DN. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. FASEB J 2014; 28:2655-66. [DOI: 10.1096/fj.13-248641] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/30/2022]
Affiliation(s)
- Matthew G. K. Benesch
- Signal Transduction Research GroupDepartment of BiochemistryUniversity of AlbertaEdmontonAlbertaCanada
| | - Xiaoyun Tang
- Signal Transduction Research GroupDepartment of BiochemistryUniversity of AlbertaEdmontonAlbertaCanada
| | - Tatsuo Maeda
- Exploration Research LaboratoriesOno Pharmaceuticals CompanyTsukubaJapan
| | - Akira Ohhata
- Medicinal Chemistry Research LaboratoriesOno Pharmaceuticals CompanyShimamotoJapan
| | - Yuan Y. Zhao
- Department of Agricultural, Food, and Nutritional ScienceUniversity of AlbertaEdmontonAlbertaCanada
| | - Bernard P. C. Kok
- Signal Transduction Research GroupDepartment of BiochemistryUniversity of AlbertaEdmontonAlbertaCanada
| | - Jay Dewald
- Signal Transduction Research GroupDepartment of BiochemistryUniversity of AlbertaEdmontonAlbertaCanada
| | - Mary Hitt
- Department of OncologyUniversity of AlbertaEdmontonAlbertaCanada
| | - Jonathan M. Curtis
- Department of Agricultural, Food, and Nutritional ScienceUniversity of AlbertaEdmontonAlbertaCanada
| | - Todd P. W. McMullen
- Department of SurgeryMackenzie Health Science CentreUniversity of AlbertaEdmontonAlbertaCanada
| | - David N. Brindley
- Signal Transduction Research GroupDepartment of BiochemistryUniversity of AlbertaEdmontonAlbertaCanada
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39
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Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions. FEBS Lett 2014; 588:2712-27. [PMID: 24560789 DOI: 10.1016/j.febslet.2014.02.009] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/15/2014] [Revised: 02/11/2014] [Accepted: 02/12/2014] [Indexed: 02/07/2023]
Abstract
Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in blood plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through at least six G-protein coupled receptors to promote cell survival, proliferation and migration. The autotaxin/lysophosphatidate signaling axis is involved in wound healing and tissue remodeling, and it drives many chronic inflammatory conditions from fibrosis to colitis, asthma and cancer. In cancer, lysophosphatidate signaling promotes resistance to chemotherapy and radiotherapy, and increases both angiogenesis and metastasis. Research into autotaxin inhibitors is accelerating, both as primary and adjuvant therapy. Historically, autotaxin inhibitors had poor bioavailability profiles and thus had limited efficacy in vivo. This situation is now changing, especially since the recent crystal structure of autotaxin is now enabling rational inhibitor design. In this review, we will summarize current knowledge on autotaxin-mediated disease processes including cancer, and discuss recent advancements in the development of autotaxin-targeting strategies. We will also provide new insights into autotaxin as an inflammatory mediator in the tumor microenvironment that promotes cancer progression and therapy resistance.
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40
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Perrakis A, Moolenaar WH. Autotaxin: structure-function and signaling. J Lipid Res 2014; 55:1010-8. [PMID: 24548887 DOI: 10.1194/jlr.r046391] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/12/2013] [Indexed: 12/13/2022] Open
Abstract
Autotaxin (ATX), or ecto-nucleotide pyrophosphatase/phosphodiesterase-2, is a secreted lysophospholipase D (lysoPLD) that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA), a ligand for specific G protein-coupled receptors. ATX-LPA signaling is essential for development and has been implicated in a great diversity of (patho)physiological processes, ranging from lymphocyte homing to tumor progression. Structural and functional studies have revealed what makes ATX a unique lysoPLD, and how secreted ATX binds to its target cells. The ATX catalytic domain shows a characteristic bimetallic active site followed by a shallow binding groove that can accommodate nucleotides as well as the glycerol moiety of lysophospholipids, and by a deep lipid-binding pocket. In addition, the catalytic domain has an open tunnel of unknown function adjacent to the active site. Here, we discuss our current understanding of ATX structure-function relationships and signaling mechanisms, and how ATX isoforms use distinct mechanisms to target LPA production to the plasma membrane, notably binding to integrins and heparan sulfate proteoglycans. We also briefly discuss the development of drug-like inhibitors of ATX.
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Affiliation(s)
- Anastassis Perrakis
- Divisions of Biochemistry, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
| | - Wouter H Moolenaar
- Cell Biology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Barbayianni E, Magrioti V, Moutevelis-Minakakis P, Kokotos G. Autotaxin inhibitors: a patent review. Expert Opin Ther Pat 2013; 23:1123-32. [PMID: 23641951 DOI: 10.1517/13543776.2013.796364] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Autotaxin (ATX) is a lysophospholipase D enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. LPA is a bioactive lipid mediator that activates several transduction pathways, and is involved in migration, proliferation and survival of various cells. Thus, ATX is an attractive medicinal target. AREAS COVERED The aim of this review is to summarize ATX inhibitors, reported in patents from 2006 up to now, describing their discovery and biological evaluation. EXPERT OPINION ATX has been implicated in various pathological conditions, such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, etc. Although there is an intensive effort on the discovery of potent and selective ATX inhibitors in order to identify novel medicinal agents, up to now, no ATX inhibitor has reached clinical trials. However, the use of ATX inhibitors seems an attractive strategy for the development of novel medicinal agents, for example anticancer therapeutics.
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Affiliation(s)
- Efrosini Barbayianni
- University of Athens, Department of Chemistry, Laboratory of Organic Chemistry, Panepistimiopolis, Athens 15771, Greece
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