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Villegas-Vazquez EY, Marín-Carrasco FP, Reyes-Hernández OD, Báez-González AS, Bustamante-Montes LP, Padilla-Benavides T, Quintas-Granados LI, Figueroa-González G. Revolutionizing ovarian cancer therapy by drug repositioning for accelerated and cost-effective treatments. Front Oncol 2025; 14:1514120. [PMID: 39876896 PMCID: PMC11772297 DOI: 10.3389/fonc.2024.1514120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/20/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Drug repositioning, the practice of identifying novel applications for existing drugs beyond their originally intended medical indications, stands as a transformative strategy revolutionizing pharmaceutical productivity. In contrast to conventional drug development approaches, this innovative method has proven to be exceptionally effective. This is particularly relevant for cancer therapy, where the demand for groundbreaking treatments continues to grow. This review focuses on drug repositioning for ovarian cancer treatment, showcasing a comprehensive exploration grounded in thorough in vitro experiments across diverse cancer cell lines, which are validated through preclinical in vivo models. These insights not only shed light on the efficacy of these drugs but also expand in potential synergies with other pharmaceutical agents, favoring the development of cost-effective treatments for cancer patients.
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Affiliation(s)
- Edgar Yebran Villegas-Vazquez
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Francisco Pável Marín-Carrasco
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Octavio Daniel Reyes-Hernández
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Andrea S. Báez-González
- Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, United States
| | | | | | - Laura Itzel Quintas-Granados
- Colegio de Ciencias y Humanidades, Plantel Cuautepec, Universidad Autónoma de la Ciudad de México, Ciudad de México, Mexico
| | - Gabriela Figueroa-González
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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2
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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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3
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Beaumont RE, Smith EJ, Zhou L, Marr N, Thorpe CT, Guest DJ. Exogenous interleukin-1 beta stimulation regulates equine tenocyte function and gene expression in three-dimensional culture which can be rescued by pharmacological inhibition of interleukin 1 receptor, but not nuclear factor kappa B, signaling. Mol Cell Biochem 2024; 479:1059-1078. [PMID: 37314623 PMCID: PMC11116237 DOI: 10.1007/s11010-023-04779-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/04/2023] [Accepted: 05/27/2023] [Indexed: 06/15/2023]
Abstract
We investigated how Interleukin 1 beta (IL-1β) impacts equine tenocyte function and global gene expression in vitro and determined if these effects could be rescued by pharmacologically inhibiting nuclear factor-κB (NF-KB) or interleukin 1 signalling. Equine superficial digital flexor tenocytes were cultured in three-dimensional (3D) collagen gels and stimulated with IL-1β for two-weeks, with gel contraction and interleukin 6 (IL6) measured throughout and transcriptomic analysis performed at day 14. The impact of three NF-KB inhibitors on gel contraction and IL6 secretion were measured in 3D culture, with NF-KB-P65 nuclear translocation by immunofluorescence and gene expression by qPCR measured in two-dimensional (2D) monolayer culture. In addition, daily 3D gel contraction and transcriptomic analysis was performed on interleukin 1 receptor antagonist-treated 3D gels at day 14. IL-1β increased NF-KB-P65 nuclear translocation in 2D culture and IL6 secretion in 3D culture, but reduced daily tenocyte 3D gel contraction and impacted > 2500 genes at day 14, with enrichment for NF-KB signaling. Administering direct pharmacological inhibitors of NF-KB did reduce NF-KB-P65 nuclear translocation, but had no effect on 3D gel contraction or IL6 secretion in the presence of IL-1β. However, IL1Ra restored 3D gel contraction and partially rescued global gene expression. Tenocyte 3D gel contraction and gene expression is adversely impacted by IL-1β which can only be rescued by blockade of interleukin 1 receptor, but not NF-KB, signalling.
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Affiliation(s)
- Ross Eric Beaumont
- Clinical Sciences and Service, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, Herts, UK.
| | - Emily Josephine Smith
- Clinical Sciences and Service, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, Herts, UK
| | - Lexin Zhou
- Clinical Sciences and Service, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, Herts, UK
| | - Neil Marr
- Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK
| | - Chavaunne T Thorpe
- Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK
| | - Deborah Jane Guest
- Clinical Sciences and Service, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, Herts, UK
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4
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Sieminska J, Miniewska K, Mroz R, Sierko E, Naumnik W, Kisluk J, Michalska-Falkowska A, Reszec J, Kozlowski M, Nowicki L, Moniuszko M, Kretowski A, Niklinski J, Ciborowski M, Godzien J. First insight about the ability of specific glycerophospholipids to discriminate non-small cell lung cancer subtypes. Front Mol Biosci 2024; 11:1379631. [PMID: 38725870 PMCID: PMC11079276 DOI: 10.3389/fmolb.2024.1379631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/31/2024] [Accepted: 04/05/2024] [Indexed: 05/12/2024] Open
Abstract
Introduction: Discrimination between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) subtypes in non-small cell lung cancer (NSCLC) patients is a significant challenge in oncology. Lipidomics analysis provides a promising approach for this differentiation. Methods: In an accompanying paper, we explored oxPCs levels in a cohort of 200 NSCLC patients. In this research, we utilized liquid chromatography coupled with mass spectrometry (LC-MS) to analyze the lipidomics profile of matching tissue and plasma samples from 25 NSCLC patients, comprising 11 ADC and 14 SCC cases. This study builds upon our previous findings, which highlighted the elevation of oxidised phosphatidylcholines (oxPCs) in NSCLC patients. Results: We identified eight lipid biomarkers that effectively differentiate between ADC and SCC subtypes using an untargeted approach. Notably, we observed a significant increase in plasma LPA 20:4, LPA 18:1, and LPA 18:2 levels in the ADC group compared to the SCC group. Conversely, tumour PC 16:0/18:2, PC 16:0/4:0; CHO, and plasma PC 16:0/18:2; OH, PC 18:0/20:4; OH, PC 16:0/20:4; OOH levels were significantly higher in the ADC group. Discussion: Our study is the first to report that plasma LPA levels can distinguish between ADC and SCC patients in NSCLC, suggesting a potential role for LPAs in NSCLC subtyping. This finding warrants further investigation into the mechanisms underlying these differences and their clinical implications.
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Affiliation(s)
- Julia Sieminska
- Metabolomics Laboratory, Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Katarzyna Miniewska
- Metabolomics Laboratory, Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Robert Mroz
- 2nd Department of Lung Diseases and Tuberculosis, Medical University of Bialystok, Bialystok, Poland
| | - Ewa Sierko
- Department of Oncology, Medical University of Bialystok, Bialystok, Poland
| | - Wojciech Naumnik
- 1st Department of Lung Diseases and Tuberculosis, Medical University of Bialystok, Bialystok, Poland
| | - Joanna Kisluk
- Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland
| | | | - Joanna Reszec
- Department of Medical Patomorphology, Medical University of Bialystok, Bialystok, Poland
| | - Miroslaw Kozlowski
- Department of Thoracic Surgery, Medical University of Bialystok, Bialystok, Poland
| | | | - Marcin Moniuszko
- Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland
| | - Adam Kretowski
- Metabolomics Laboratory, Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland
| | - Michal Ciborowski
- Metabolomics Laboratory, Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Joanna Godzien
- Metabolomics Laboratory, Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
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5
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Kaffe E, Tisi A, Magkrioti C, Aidinis V, Mehal WZ, Flavell RA, Maccarrone M. Bioactive signalling lipids as drivers of chronic liver diseases. J Hepatol 2024; 80:140-154. [PMID: 37741346 DOI: 10.1016/j.jhep.2023.08.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/15/2023] [Revised: 08/23/2023] [Accepted: 08/28/2023] [Indexed: 09/25/2023]
Abstract
Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso-phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors.
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Affiliation(s)
- Eleanna Kaffe
- Department of Immunobiology, Yale University School of Medicine, 06511, New Haven, CT, USA.
| | - Annamaria Tisi
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | | | - Vassilis Aidinis
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece
| | - Wajahat Z Mehal
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, 06520, USA; Veterans Affairs Medical Center, West Haven, CT, 06516, USA
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, 06511, New Haven, CT, USA; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, 06519, USA
| | - Mauro Maccarrone
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy; Laboratory of Lipid Neurochemistry, European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, 00143 Rome, Italy.
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6
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Shinde A, Tang X, Singh R, Brindley DN. Infliximab, a Monoclonal Antibody against TNF-α, Inhibits NF-κB Activation, Autotaxin Expression and Breast Cancer Metastasis to Lungs. Cancers (Basel) 2023; 16:52. [PMID: 38201482 PMCID: PMC10778319 DOI: 10.3390/cancers16010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/24/2023] [Revised: 12/16/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
An inflammatory milieu in the tumor microenvironment leads to immune evasion, resistance to cell death, metastasis and poor prognosis in breast cancer patients. TNF-α is a proinflammatory cytokine that regulates multiple aspects of tumor biology from initiation to progression. TNF-α-induced NF-κB activation initiates inflammatory pathways, which determine cell survival, death and tumor progression. One candidate pathway involves the increased secretion of autotaxin, which produces lysophosphatidate that signals through six G-protein-coupled receptors. Significantly, autotaxin is one of the 40-50 most upregulated genes in metastatic tumors. In this study, we investigated the effects of TNF-α by blocking its action with a monoclonal antibody, Infliximab, and studied the effects on autotaxin secretion and tumor progression. Infliximab had little effect on tumor growth, but it decreased lung metastasis by 60% in a syngeneic BALB/c mouse model using 4T1 breast cancer cells. Infliximab-treated mice also showed a decrease in proliferation and metastatic markers like Ki-67 and vimentin in tumors. This was accompanied by decreases in NF-κB activation, autotaxin expression and the concentrations of plasma and tumor cytokines/chemokines which are involved in metastasis. We also demonstrated a positive correlation of TNF-α -NF-κB and ATX expression in breast cancer patients using cancer databases. Studies in vitro showed that TNF-α-induced NF-κB activation increases autotaxin expression and the clone forming ability of 4T1 breast cancer cells. This report highlights the potential role of Infliximab as an additional approach to attenuate signaling through the autotaxin-lysophosphatidate-inflammatory cycle and decrease mortality from metastatic cancer.
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Affiliation(s)
- Anjali Shinde
- Department of Biochemistry, Faculty of Science, The MS University of Baroda, Vadodara 390002, Gujarat, India;
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
| | - Xiaoyun Tang
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
| | - Rajesh Singh
- Department of Biochemistry, Faculty of Science, The MS University of Baroda, Vadodara 390002, Gujarat, India;
- Department of Molecular and Human Genetics, Banaras Hindu University (BHU), Varanasi 221005, Uttar Pradesh, India
| | - David N. Brindley
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
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7
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Konen JM, Rodriguez BL, Wu H, Fradette JJ, Gibson L, Diao L, Wang J, Schmidt S, Wistuba II, Zhang J, Gibbons DL. Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti-PD-1 resistance in non-small cell lung cancer. J Clin Invest 2023; 133:e163128. [PMID: 37655662 PMCID: PMC10471170 DOI: 10.1172/jci163128] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/29/2022] [Accepted: 07/13/2023] [Indexed: 09/02/2023] Open
Abstract
Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and effector tumor-infiltrating CD8+ T cells. Pharmacological inhibition of ATX, or the downstream receptor LPAR5, in combination with anti-PD-1 was sufficient to restore the antitumor immune response and efficaciously control lung tumor growth in multiple KP tumor models. Additionally, ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma patient data sets, suggesting that an activated tumor-immune microenvironment upregulates ATX and thus provides an opportunity for cotargeting to prevent acquired resistance to anti-PD-1 treatment. These data reveal the ATX/LPA axis as an immunosuppressive pathway that diminishes the immune checkpoint blockade response in lung cancer.
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Affiliation(s)
- Jessica M. Konen
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA
| | - B. Leticia Rodriguez
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Haoyi Wu
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jared J. Fradette
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Laura Gibson
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Surgical Oncology
| | - Lixia Diao
- Department of Bioinformatics and Computational Biology
| | - Jing Wang
- Department of Bioinformatics and Computational Biology
| | | | - Ignacio I. Wistuba
- Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, and
| | - Jianjun Zhang
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Don L. Gibbons
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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8
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Long Y, Wang Y, Qu M, Zhang D, Zhang X, Zhang J. Combined inhibition of EZH2 and the autotaxin-LPA-LPA2 axis exerts synergistic antitumor effects on colon cancer cells. Cancer Lett 2023; 566:216226. [PMID: 37230222 DOI: 10.1016/j.canlet.2023.216226] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/19/2023] [Revised: 05/04/2023] [Accepted: 05/13/2023] [Indexed: 05/27/2023]
Abstract
Autotaxin (ATX), also known as ENPP2, is the key enzyme in lysophosphatidic acid (LPA) production. LPA acts on its receptors on the cell membrane to promote cell proliferation and migration, and thus, the ATX-LPA axis plays a critical role in tumorigenesis. Clinical data analysis indicated that in colon cancer, there is a strong negative correlation between the expression of ATX and EZH2, the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2). Here, we demonstrated that ATX expression was epigenetically silenced by PRC2, which was recruited by MTF2 and catalyzed H3K27me3 modification in the ATX promoter region. EZH2 inhibition is a promising strategy for cancer treatment, and ATX expression is induced in colon cancer cells by EZH2 inhibitors. With both EZH2 and ATX as targets, their combined inhibition exerted synergistic antitumor effects on colon cancer cells. In addition, LPA receptor 2 (LPA2) deficiency significantly enhanced the sensitivity to EZH2 inhibitors in colon cancer cells. In summary, our study identified ATX as a novel PRC2 target gene and found that cotargeting EZH2 and the ATX-LPA-LPA2 axis may be a potential combination therapy strategy for colon cancer.
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Affiliation(s)
- Yang Long
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing, 100875, China
| | - Yuqin Wang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing, 100875, China
| | - Mengxia Qu
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing, 100875, China
| | - Di Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing, 100875, China
| | - Xiaotian Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing, 100875, China.
| | - Junjie Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing, 100875, China.
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9
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Lin KH, Lee SC, Dacheux MA, Norman DD, Balogh A, Bavaria M, Lee H, Tigyi G. E2F7 drives autotaxin/Enpp2 transcription via chromosome looping: Repression by p53 in murine but not in human carcinomas. FASEB J 2023; 37:e23058. [PMID: 37358838 PMCID: PMC10364077 DOI: 10.1096/fj.202300838r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/26/2023] [Revised: 05/31/2023] [Accepted: 06/13/2023] [Indexed: 06/27/2023]
Abstract
Dysregulation of the autotaxin (ATX, Enpp2)-lysophosphatidic acid (LPA) signaling in cancerous cells contributes to tumorigenesis and therapy resistance. We previously found that ATX activity was elevated in p53-KO mice compared to wild-type (WT) mice. Here, we report that ATX expression was upregulated in mouse embryonic fibroblasts from p53-KO and p53R172H mutant mice. ATX promoter analysis combined with yeast one-hybrid testing revealed that WT p53 directly inhibits ATX expression via E2F7. Knockdown of E2F7 reduced ATX expression and chromosome immunoprecipitation showed that E2F7 promotes Enpp2 transcription through cooperative binding to two E2F7 sites (promoter region -1393 bp and second intron 996 bp). Using chromosome conformation capture, we found that chromosome looping brings together the two E2F7 binding sites. We discovered a p53 binding site in the first intron of murine Enpp2, but not in human ENPP2. Binding of p53 disrupted the E2F7-mediated chromosomal looping and repressed Enpp2 transcription in murine cells. In contrast, we found no disruption of E2F7-mediated ENPP2 transcription via direct p53 binding in human carcinoma cells. In summary, E2F7 is a common transcription factor that upregulates ATX in human and mouse cells but is subject to steric interference by direct intronic p53 binding only in mice.
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Affiliation(s)
- Kuan-Hung Lin
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Mélanie A Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Andrea Balogh
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Mitul Bavaria
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Hsinyu Lee
- Department of Life Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Gabor Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
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10
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Chen X, Zhang H, Zhou X, Wang Y, Shi W. Autotaxin promotes the degradation of the mucus layer by inhibiting autophagy in mouse colitis. Mol Immunol 2023; 160:44-54. [PMID: 37356325 DOI: 10.1016/j.molimm.2023.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/02/2023] [Revised: 05/06/2023] [Accepted: 06/06/2023] [Indexed: 06/27/2023]
Abstract
Autotaxin (ATX or ENPP2) is an autocrine enzyme associated with the metabolism of various phospholipids. ATX has recently been identified as a regulatory factor in immune-related and inflammation-associated diseases, such as inflammatory bowel disease, but the exact mechanism is unclear. Here, we treated mice with recombinant ATX protein or an ATX inhibitor to investigate the effect of ATX on colitis in mice and the underlying mechanism. In a mouse model of colitis, ATX expression was increased, autophagy was impaired, and the mucus barrier was disrupted. Recombinant ATX protein promoted intestinal inflammation, inhibited autophagy, and disrupted the mucus barrier, while an ATX inhibitor had the opposite effect. Next, we treated mice that received ATX with an autophagy activator and an adenosine 5'-monophosphate-activated protein kinase (AMPK) agonist. We observed that autophagy activator and AMPK agonist could repair the mucus barrier and alleviate intestinal inflammation in ATX-treated mice. In vitro, we obtained consistent results. Thus, we concluded that ATX could inhibit autophagy through the AMPK pathway, which consequently disordered the mucus barrier and aggravated intestinal inflammation.
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Affiliation(s)
- Xiaoyan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China; The State Key Laboratory of Digestive Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hui Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaojiang Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yunwu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wenjie Shi
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
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11
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Dacheux MA, Norman DD, Tigyi GJ, Lee SC. Emerging roles of lysophosphatidic acid receptor subtype 5 (LPAR5) in inflammatory diseases and cancer. Pharmacol Ther 2023; 245:108414. [PMID: 37061203 DOI: 10.1016/j.pharmthera.2023.108414] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/17/2023]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that regulates a variety of cellular functions such as cell proliferation, migration, survival, calcium mobilization, cytoskeletal rearrangements, and neurite retraction. The biological actions of LPA are mediated by at least six G protein-coupled receptors known as LPAR1-6. Given that LPAR1-3 were among the first LPARs identified, the majority of research efforts have focused on understanding their biology. This review provides an in-depth discussion of LPAR5, which has recently emerged as a key player in regulating normal intestinal homeostasis and modulating pathological conditions such as pain, itch, inflammatory diseases, and cancer. We also present a chronological overview of the efforts made to develop compounds that target LPAR5 for use as tool compounds to probe or validate LPAR5 biology and therapeutic agents for the treatment of inflammatory diseases and cancer.
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Affiliation(s)
- Mélanie A Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Gábor J Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America.
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12
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Méaux MN, Regnier M, Portefaix A, Borel O, Alioli C, Peyruchaud O, Legrand M, Bacchetta J. Circulating autotaxin levels in healthy teenagers: Data from the Vitados cohort. Front Pediatr 2023; 11:1094705. [PMID: 36861069 PMCID: PMC9969100 DOI: 10.3389/fped.2023.1094705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/10/2022] [Accepted: 01/16/2023] [Indexed: 02/17/2023] Open
Abstract
Autotaxin (ATX) is a secreted enzyme with a lysophospholipase D activity, mainly secreted by adipocytes and widely expressed. Its major function is to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), an essential bioactive lipid involved in multiple cell processes. The ATX-LPA axis is increasingly studied because of its involvement in numerous pathological conditions, more specifically in inflammatory or neoplastic diseases, and in obesity. Circulating ATX levels gradually increase with the stage of some pathologies, such as liver fibrosis, thus making them a potentially interesting non-invasive marker for fibrosis estimation. Normal circulating levels of ATX have been established in healthy adults, but no data exist at the pediatric age. The aim of our study is to describe the physiological concentrations of circulating ATX levels in healthy teenagers through a secondary analysis of the VITADOS cohort. Our study included 38 teenagers of Caucasian origin (12 males, 26 females). Their median age was 13 years for males and 14 years for females, ranging from Tanner 1 to 5. BMI was at the 25th percentile for males and 54th percentile for females, and median blood pressure was normal. ATX median levels were 1,049 (450-2201) ng/ml. There was no difference in ATX levels between sexes in teenagers, which was in contrast to the male and female differences described in the adult population. ATX levels significantly decreased with age and pubertal status, reaching adult levels at the end of puberty. Our study also suggested positive correlations between ATX levels and blood pressure (BP), lipid metabolism, and bone biomarkers. However, except for LDL cholesterol, these factors were also significantly correlated with age, which might be a confounding factor. Still, a correlation between ATX and diastolic BP was described in obese adult patients. No correlation was found between ATX levels and inflammatory marker C-reactive protein (CRP), Body Mass Index (BMI), and biomarkers of phosphate/calcium metabolism. In conclusion, our study is the first to describe the decline in ATX levels with puberty and the physiological concentrations of ATX levels in healthy teenagers. It will be of utmost importance when performing clinical studies in children with chronic diseases to keep these kinetics in mind, as circulating ATX might become a non-invasive prognostic biomarker in pediatric chronic diseases.
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Affiliation(s)
- Marie-Noëlle Méaux
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Maitena Regnier
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Aurélie Portefaix
- Centre d'Investigation Clinique, CIC 1407, Hospices Civils de Lyon, Bron, France
| | | | | | | | - Mélanie Legrand
- INSERM, UMR 1033, Lyon, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France.,Service de Rhumatologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Justine Bacchetta
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
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13
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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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14
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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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15
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Wang S, Chen J, Guo XZ. KAI1/CD82 gene and autotaxin-lysophosphatidic acid axis in gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:1388-1405. [PMID: 36160748 PMCID: PMC9412925 DOI: 10.4251/wjgo.v14.i8.1388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/11/2021] [Revised: 01/06/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.
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Affiliation(s)
- Shuo Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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16
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Qu X, Wang T, Liu X, Jiang X, Liang X, Wu J. Dual-Mechanism-Driven Strategy for High-Coverage Detection of Serum Lipids on a Novel SALDI-MS Target. Anal Chem 2022; 94:8570-8579. [PMID: 35670384 DOI: 10.1021/acs.analchem.1c04929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
Serum lipid metabolites have been emerging as ideal biomarkers for disease diagnosis and prediction. In the current stage, nontargeted or targeted lipidomic research mainly relies on a liquid chromatography-mass spectrometry (LC-MS) platform, but future clinical applications need more robust and high-speed platforms. Surface-assisted laser desorption ionization mass spectrometry (SALDI-MS) has shown excellent advantages in the high-speed analysis of lipid metabolites. However, the platform in the positive ion mode is more inclined to target a certain class of lipids, leading to the low coverage of lipid detection and limiting its practical translation to clinical applications. Herein, we proposed a dual-mechanism-driven strategy for high-coverage detection of serum lipids on a novel SALDI-MS target, which is a composite nanostructure comprising vertical silicon nanowires (VSiNWs) decorated with AuNPs and polydopamine (VSiNW-Au-PDA). The performance of laser desorption and ionization on the target can be enhanced by charge-driven desorption coupled with thermal-driven desorption. Simultaneous detection of 236 serum lipids (S/N ≥ 5) including neutral and polar lipids can be achieved in the positive ion mode. Among these, 107 lipid peaks were successfully identified. When combined with VSiNW-Au-PDA and VSiNW chips, 479 lipid peaks can be detected in serum samples in positive and negative ion modes, respectively. Based on the platform, serum samples from 57 hepatocellular carcinoma (HCC) patients and 76 healthy controls were analyzed. After data mining, 14 lipids containing different lipid types (TAG, CE, PC) were selected as potential lipidomic biomarkers. With the assistance of an artificial neural network, a diagnostic model with a sensitivity of 92.7% and a specificity of 96% was constructed for HCC diagnosis.
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Affiliation(s)
- Xuetong Qu
- Institute of Analytical Chemistry, Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Tao Wang
- Institute of Analytical Chemistry, Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Xingyue Liu
- Institute of Analytical Chemistry, Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Xinrong Jiang
- Institute of Analytical Chemistry, Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Jianmin Wu
- Institute of Analytical Chemistry, Department of Chemistry, Zhejiang University, Hangzhou 310058, China
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17
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Karshovska E, Mohibullah R, Zhu M, Zahedi F, Thomas D, Magkrioti C, Geissler C, Megens RTA, Bianchini M, Nazari-Jahantigh M, Ferreirós N, Aidinis V, Schober A. ENPP2 (Endothelial Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male Mice. Arterioscler Thromb Vasc Biol 2022; 42:1023-1036. [PMID: 35708027 DOI: 10.1161/atvbaha.122.317682] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Maladapted endothelial cells (ECs) secrete ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2; autotaxin)-a lysophospholipase D that generates lysophosphatidic acids (LPAs). ENPP2 derived from the arterial wall promotes atherogenic monocyte adhesion induced by generating LPAs, such as arachidonoyl-LPA (LPA20:4), from oxidized lipoproteins. Here, we aimed to determine the role of endothelial ENPP2 in the production of LPAs and atherosclerosis. METHODS We quantified atherosclerosis in mice harboring loxP-flanked Enpp2 alleles crossed with Apoe-/- mice expressing tamoxifen-inducible Cre recombinase under the control of the EC-specific bone marrow X kinase promoter after 12 weeks of high-fat diet feeding. RESULTS A tamoxifen-induced EC-specific Enpp2 knockout decreased atherosclerosis, accumulation of lesional macrophages, monocyte adhesion, and expression of endothelial CXCL (C-X-C motif chemokine ligand) 1 in male and female Apoe-/- mice. In vitro, ENPP2 mediated the mildly oxidized LDL (low-density lipoprotein)-induced expression of CXCL1 in aortic ECs by generating LPA20:4, palmitoyl-LPA (LPA16:0), and oleoyl-LPA (LPA18:1). ENPP2 and its activity were detected on the endothelial surface by confocal imaging. The expression of endothelial Enpp2 established a strong correlation between the plasma levels of LPA16:0, stearoyl-LPA (LPA18:0), and LPA18:1 and plaque size and a strong negative correlation between the LPA levels and ENPP2 activity in the plasma. Moreover, endothelial Enpp2 knockout increased the weight of high-fat diet-fed male Apoe-/- mice. CONCLUSIONS We demonstrated that the expression of ENPP2 in ECs promotes atherosclerosis and endothelial inflammation in a sex-independent manner. This might be due to the generation of LPA20:4, LPA16:0, and LPA18:1 from mildly oxidized lipoproteins on the endothelial surface.
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Affiliation(s)
- Ela Karshovska
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.)
| | - Rokia Mohibullah
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.)
| | - Mengyu Zhu
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.).,Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands (M.Z., R.T.A.M.)
| | - Farima Zahedi
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.).,Now with Department of Biomedical Science and Mari Lowe Center for Comparative Oncology, University of Pennsylvania, Philadelphia (F.Z.)
| | - Dominique Thomas
- Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany (D.T., N.F.).,Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt, Germany (D.T.)
| | - Christiana Magkrioti
- Division of Immunology, Biomedical Science Research, Center Alexander Fleming, Athens, Greece (C.M., V.A.)
| | - Claudia Geissler
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.)
| | - Remco T A Megens
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.).,Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands (M.Z., R.T.A.M.)
| | - Mariaelvy Bianchini
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.)
| | - Maliheh Nazari-Jahantigh
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.).,German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Germany (M.N.-J., A.S.)
| | - Nerea Ferreirós
- Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany (D.T., N.F.)
| | - Vassilis Aidinis
- Division of Immunology, Biomedical Science Research, Center Alexander Fleming, Athens, Greece (C.M., V.A.)
| | - Andreas Schober
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.).,German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Germany (M.N.-J., A.S.)
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18
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Wan Z, Wang X. Role of SLC39A6 in the development and progression of liver cancer. Oncol Lett 2022; 23:77. [PMID: 35111246 PMCID: PMC8771636 DOI: 10.3892/ol.2022.13197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/29/2021] [Accepted: 12/21/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is one of the most common malignant solid tumor types worldwide. The solute carrier (SLC)39A family is a main member of the SLC group of membrane transport proteins, which transfer zinc to the cytoplasm when cells are depleted of zinc; thus, it may provide a novel therapeutic target for human cancer. However, the prognostic value of SLC39A genes in patients with liver cancer has remained elusive. Therefore, the present study aimed to explore whether SLC39A family genes are associated with the survival rate of patients with liver cancer and to investigate the role of key genes of the SLC39A family in liver cancer. The mRNA expression of the SLC39A family in liver cancer was obtained from the UALCAN database. Survival curve analysis was performed to investigate the prognostic value of SLC39A family genes in the overall survival of patients with liver cancer. In addition to the bioinformatics analysis, SLC39A6 was knocked down in HepG2 and Hep3B cells to examine the effect on the proliferation, migration and invasion of liver cancer cells. The results suggested that SLC39A6 was significantly upregulated in liver cancer tissues compared with normal liver tissues. High expression of SLC39A6 was significantly associated with poor overall survival of patients with liver cancer. Furthermore, knockdown of SLC39A6 inhibited the proliferation, migration and invasion of liver cancer cells in vitro and in vivo. Collectively, the results of the present study suggested that SLC39A6 may be a promising prognostic biomarker for liver cancer and is associated with the proliferation, migration and invasion of liver cancer.
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Affiliation(s)
- Zhen Wan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xuzhen Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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19
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She S, Zhang Q, Shi J, Yang F, Dai K. Roles of Autotaxin/Autotaxin-Lysophosphatidic Acid Axis in the Initiation and Progression of Liver Cancer. Front Oncol 2022; 12:922945. [PMID: 35769713 PMCID: PMC9236130 DOI: 10.3389/fonc.2022.922945] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/18/2022] [Accepted: 05/13/2022] [Indexed: 02/05/2023] Open
Abstract
Autotaxin (ATX) is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a growth factor-like signaling phospholipid. ATX has been abundantly detected in the culture medium of various cancer cells, tumor tissues, and serum or plasma of cancer patients. Biological actions of ATX are mediated by LPA. The ATX-LPA axis mediates a plethora of activities, such as cell proliferation, survival, migration, angiogenesis, and inflammation, and participates in the regulation of various physiological and pathological processes. In this review, we have summarized the physiological function of ATX and the ATX-LPA axis in liver cancer, analyzed the role of the ATX-LPA axis in tumorigenesis and metastasis, and discussed the therapeutic strategies targeting the ATX-LPA axis, paving the way for new therapeutic developments.
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Affiliation(s)
| | | | | | - Fan Yang
- *Correspondence: Fan Yang, ; Kai Dai,
| | - Kai Dai
- *Correspondence: Fan Yang, ; Kai Dai,
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20
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ENPP2 Methylation in Health and Cancer. Int J Mol Sci 2021; 22:ijms222111958. [PMID: 34769391 PMCID: PMC8585013 DOI: 10.3390/ijms222111958] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/29/2021] [Revised: 10/21/2021] [Accepted: 11/01/2021] [Indexed: 11/16/2022] Open
Abstract
Autotaxin (ATX) encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a key enzyme in Lysophosphatidic Acid (LPA) synthesis implicated in cancer. Although its aberrant expression has been reported, ENPP2 methylation profiles in health and malignancy are not described. We examined in silico the methylation of ENPP2 analyzing publicly available methylome datasets, to identify Differentially Methylated CpGs (DMCs) which were then correlated with expression at gene and isoform levels. Significance indication was set to be FDR corrected p-value < 0.05. Healthy tissues presented methylation in all gene body CGs and lower levels in Promoter Associated (PA) regions, whereas in the majority of the tumors examined (HCC, melanoma, CRC, LC and PC) the methylation pattern was reversed. DMCs identified in the promoter were located in sites recognized by multiple transcription factors, suggesting involvement in gene expression. Alterations in methylation were correlated to an aggressive phenotype in cancer cell lines. In prostate and lung adenocarcinomas, increased methylation of PA CGs was correlated to decreased ENPP2 mRNA expression and to poor prognosis parameters. Collectively, our results corroborate that methylation is an active level of ATX expression regulation in cancer. Our study provides an extended description of the methylation status of ENPP2 in health and cancer and points out specific DMCs of value as prognostic biomarkers.
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21
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Structural and PK-guided identification of indole-based non-acidic autotaxin (ATX) inhibitors exhibiting high in vivo anti-fibrosis efficacy in rodent model. Eur J Med Chem 2021; 227:113951. [PMID: 34742015 DOI: 10.1016/j.ejmech.2021.113951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/24/2021] [Revised: 10/13/2021] [Accepted: 10/23/2021] [Indexed: 11/23/2022]
Abstract
In recent decades, pharmacological targeting of the autotaxin (ATX)/lysophosphatidic acid (LPA) axis accounted for excellent disease management benefits. Herein, to extend the scope of structure-activity relationships (SARs), fifteen indole-based carbamate derivatives (1-15) were prepared to evaluate the ATX inhibitory potency. Among them, compound 4 bearing morpholine moiety was identified as the optimal ATX inhibitor (0.41 nM), superior to the positive control GLPG1690 (2.90 nM). To resolve the intractable issue of poor pharmacokinetic (PK) property, urea moiety was introduced as a surrogate of carbamate which furnished compounds 16-30. The dedicated modification identified the diethanolamine entity 30 with satisfactory water solubility and PK profiles with a minimum sacrifice of ATX inhibition (2.17 nM). The most promising candidate 30 was evaluated for anti-fibrosis effect in a bleomycin challenged mice lung fibrosis model. Upon treatment with 30, the in vivo ATX activity in both lung homogenate and broncheoalveolar fluid (BALF) sample was significantly down-regulated. Furthermore, the gene expression of pro-fibrotic cytokines transforming growth factor-β (TGF-β), interleukin- 6 (IL-6) and tumor necrosis factor-α (TNF-α) in lung tissue was reduced to normal level. Collectively, the promising biological effects may advocate potential application of 30 in fibrosis relevant diseases.
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Development of a KRAS-Associated Metabolic Risk Model for Prognostic Prediction in Pancreatic Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9949272. [PMID: 34660806 PMCID: PMC8516536 DOI: 10.1155/2021/9949272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 03/30/2021] [Revised: 09/01/2021] [Accepted: 09/11/2021] [Indexed: 02/06/2023]
Abstract
Background KRAS was reported to affect some metabolic genes and promote metabolic reprogramming in solid tumors. However, there was no comprehensive analysis to explore KRAS-associated metabolic signature or risk model for pancreatic cancer (PC). Methods In the current study, multiple bioinformatics analyses were used to identify differentially expressed metabolic genes based on KRAS mutation status in PC. Then, we developed and validated a prognostic risk model based on the selected KRAS-associated metabolic genes. Besides, we explored the association between the risk model and the metabolic characteristics as well as gemcitabine-associated chemoresistance in PC. Results 6 KRAS-associated metabolic genes (i.e., CYP2S1, GPX3, FTCD, ENPP2, UGT1A10, and XDH) were selected and enrolled to establish a prognostic risk model. The prognostic model had a high C-index of 0.733 for overall survival (OS) in TCGA pancreatic cancer database. The area under the curve (AUC) values of 1- and 3-year survival were both greater than 0.70. Then, the risk model was validated in two GEO datasets and also presented a satisfactory discrimination and calibration performance. Further, we found that the expression of some KRAS-driven glycolysis-associated genes (PKM, GLUT1, HK2, and LDHA) and gemcitabine-associated chemoresistance genes (i.e., CDA and RMM2) was significantly upregulated in high-risk PC patients evaluated by the risk model. Conclusions We constructed a risk model based on 6 KRAS-associated metabolic genes, which predicted patients' survival with high accuracy and reflected tumor metabolic characteristics and gemcitabine-associated chemoresistance in PC.
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Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166239. [PMID: 34389475 DOI: 10.1016/j.bbadis.2021.166239] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/06/2021] [Revised: 07/22/2021] [Accepted: 07/31/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autotaxin is an enzyme that converts lysophospholipid into lysophosphatidic acid (LPA), a highly potent signaling molecule through a range of LPA receptors. It is therefore important to investigate which factors play a role in regulating ATX expression. Since we have reported that ATX levels increase dramatically in patients with various forms of cholestasis, we embarked on a study to reveal factors that influence the enzyme activity ATX as well as its expression level in vitro and in vivo. METHODS Bile from cholestatic patients was fractionated by HPLC and analyzed for modulation of ATX activity. ATX expression was measured in fibroblasts upon stimulation or inhibition of LPA signaling. RESULTS Surprisingly, ATX activity was stimulated by most forms of its product LPA, but it was inhibited by bile salts and bile salt-like molecules, particularly by 3-OH sulfated bile salts and sulfated progesterone metabolites that are known to accumulate during chronic cholestasis and cholestasis of pregnancy, respectively. Activation of fibroblasts by LPA decreased ATX expression by 72%. Conversely, inhibition of LPA signaling increased ATX expression 3-fold, indicating strong feedback regulation by LPA signaling. In fibroblasts, we could verify that inhibition of ATX activity by bile salts induces its expression. Furthermore, induction of cholestasis in mice causes increased plasma ATX activity. CONCLUSIONS Multiple biliary compounds that accumulate in the systemic circulation during cholestasis inhibit ATX activity and thereby increase ATX expression through feedback regulation. This mechanism may contribute to increased serum ATX activity in patients with cholestasis.
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Luna C, Parker M, Challa P, Gonzalez P. Long-Term Decrease of Intraocular Pressure in Rats by Viral Delivery of miR-146a. Transl Vis Sci Technol 2021; 10:14. [PMID: 34254987 PMCID: PMC8287046 DOI: 10.1167/tvst.10.8.14] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/28/2022] Open
Abstract
Purpose To evaluate the effects of miR-146a in trabecular meshwork (TM) cells and on intraocular pressure (IOP) in vivo via viral delivery of miR-146a to the anterior chamber of rat eyes. Methods Human TM cells were transfected with miR-146 mimic or inhibitor. Some cells from each group were then subjected to cyclic mechanical stress (CMS). Other cells from each group had no force applied. Gene expression was then analyzed by quantitative polymerase chain reaction (qPCR). Replication-deficient adenovirus and lentivirus expressing miR-146a were inoculated into the anterior segment of Brown Norway rat eyes. IOP was monitored by rebound tonometry, visual acuity was evaluated by optokinetic tracking (OKT), and inflammation markers in the anterior segment were examined by slit-lamp, qPCR, and semi-thin sections. Results miR-146 affected the expression of genes potentially involved in outflow homeostasis at basal levels and under CMS. Both lentiviral and adenoviral vectors expressing miR-146a resulted in sustained decreases in IOP ranging from 2.6 to 4.4 mmHg. Long term follow-up of rats injected with lentiviral vectors showed a sustained effect on IOP of 4.4 ± 2.9 mmHg that lasted until rats were sacrificed more than 8 months later. Eyes showed no signs of inflammation, loss of visual acuity, or other visible abnormalities. Conclusions Intracameral delivery of miR-146a can provide a long-term decrease of IOP in rats without signs of inflammation or other visible adverse effects. Transitional Relevance The IOP-lowering effects of miR-146 observed in rats provides a necessary step toward the development of an effective gene therapy for glaucoma in humans.
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Aiello S, Casiraghi F. Lysophosphatidic Acid: Promoter of Cancer Progression and of Tumor Microenvironment Development. A Promising Target for Anticancer Therapies? Cells 2021; 10:cells10061390. [PMID: 34200030 PMCID: PMC8229068 DOI: 10.3390/cells10061390] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/22/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Increased expression of the enzyme autotaxin (ATX) and the consequently increased levels of its product, lysophosphatidic acid (LPA), have been reported in several primary tumors. The role of LPA as a direct modulator of tumor cell functions—motility, invasion and migration capabilities as well as resistance to apoptotic death—has been recognized by numerous studies over the last two decades. Notably, evidence has recently been accumulating that shows that LPA also contributes to the development of the tumor microenvironment (TME). Indeed, LPA plays a crucial role in inducing angiogenesis and lymphangiogenesis, triggering cellular glycolytic shift and stimulating intratumoral fibrosis. In addition, LPA helps tumoral cells to escape immune surveillance. Treatments that counter the TME components, in order to deprive cancer cells of their crucial support, have been emerging among the promising new anticancer therapies. This review aims to summarize the latest knowledge on how LPA influences both tumor cell functions and the TME by regulating the activity of its different elements, highlighting why and how LPA is worth considering as a molecular target for new anticancer therapies.
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Therapeutic Strategies for Targeting Ovarian Cancer Stem Cells. Int J Mol Sci 2021; 22:ijms22105059. [PMID: 34064635 PMCID: PMC8151268 DOI: 10.3390/ijms22105059] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/30/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is a fatal gynecological malignancy. Although first-line chemotherapy and surgical operation are effective treatments for ovarian cancer, its clinical management remains a challenge owing to intrinsic or acquired drug resistance and relapse at local or distal lesions. Cancer stem cells (CSCs) are a small subpopulation of cells inside tumor tissues, and they can self-renew and differentiate. CSCs are responsible for the cancer malignancy involved in relapses as well as resistance to chemotherapy and radiation. These malignant properties of CSCs are regulated by cell surface receptors and intracellular pluripotency-associated factors triggered by internal or external stimuli from the tumor microenvironment. The malignancy of CSCs can be attenuated by individual or combined restraining of cell surface receptors and intracellular pluripotency-associated factors. Therefore, targeted therapy against CSCs is a feasible therapeutic tool against ovarian cancer. In this paper, we review the prominent roles of cell surface receptors and intracellular pluripotency-associated factors in mediating the stemness and malignancy of ovarian CSCs.
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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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Liu S, Jiang H, Min L, Ning T, Xu J, Wang T, Wang X, Zhang Q, Cao R, Zhang S, Zhu S. Lysophosphatidic acid mediated PI3K/Akt activation contributed to esophageal squamous cell cancer progression. Carcinogenesis 2020; 42:611-620. [PMID: 33367557 DOI: 10.1093/carcin/bgaa143] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/26/2020] [Revised: 11/30/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA) and its G-protein-coupled receptors (Lpar1-Lpar6) mediate a plethora of activities associated with cancer growth and progression. However, there is no systematic study about whether and how LPA promotes esophageal squamous cell carcinoma (ESCC). Here, we show that autotaxin (ATX), a primary LPA-producing enzyme, is highly expressed in ESCC, and overexpressed ATX is associated with the poor outcome of ESCC patients. Meanwhile, the expression of Lpar1 was much higher in ESCC cells compared with Het-1a (human esophagus normal epithelial cells). Functional experiments showed that LPA remarkably increased the proliferation and migration of ESCC cells. Furthermore, Lpar1 knockdown abolished the effect of LPA on ESCC cell proliferation and migration. Mechanistic studies revealed that LPA promoted ESCC cell lines proliferation and migration through PI3K/Akt pathway. Treatment of KYSE30 cell xenografts with Lpar1 inhibitor BMS-986020 significantly repressed tumor growth. Our results shed light on the important role of LPA in ESCC, and Lpar1 might be a potential treatment target for ESCC.
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Affiliation(s)
- Si Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Haiyan Jiang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China.,Department of Gastroenterology, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing 100029, PR China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Tingting Ning
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Junxuan Xu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Tiange Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Xingyu Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Qian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Ruizhen Cao
- Department of Gastroenterology, Ordos Central Hospital, National Clinical Research Center for Digestive Disease-Ordos Subcenter, Ordos 017000, Innermongolia, PR China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, PR China
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Xu X, Zhang Y, Zhang J, Zhang X. NSun2 promotes cell migration through methylating autotaxin mRNA. J Biol Chem 2020; 295:18134-18147. [PMID: 33093178 PMCID: PMC7939462 DOI: 10.1074/jbc.ra119.012009] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/01/2019] [Revised: 10/11/2020] [Indexed: 01/11/2023] Open
Abstract
NSun2 is an RNA methyltransferase introducing 5-methylcytosine into tRNAs, mRNAs, and noncoding RNAs, thereby influencing the levels or function of these RNAs. Autotaxin (ATX) is a secreted glycoprotein and is recognized as a key factor in converting lysophosphatidylcholine into lysophosphatidic acid (LPA). The ATX-LPA axis exerts multiple biological effects in cell survival, migration, proliferation, and differentiation. Here, we show that NSun2 is involved in the regulation of cell migration through methylating ATX mRNA. In the human glioma cell line U87, knockdown of NSun2 decreased ATX protein levels, whereas overexpression of NSun2 elevated ATX protein levels. However, neither overexpression nor knockdown of NSun2 altered ATX mRNA levels. Further studies revealed that NSun2 methylated the 3'-UTR of ATX mRNA at cytosine 2756 in vitro and in vivo Methylation by NSun2 enhanced ATX mRNA translation. In addition, NSun2-mediated 5-methylcytosine methylation promoted the export of ATX mRNA from nucleus to cytoplasm in an ALYREF-dependent manner. Knockdown of NSun2 suppressed the migration of U87 cells, which was rescued by the addition of LPA. In summary, we identify NSun2-mediated methylation of ATX mRNA as a novel mechanism in the regulation of ATX.
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Affiliation(s)
- Xin Xu
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Yihua Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Junjie Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China; Academy of Plateau Science and Sustainability, People's Government of Qinghai Province & Beijing Normal University, Xining, China.
| | - Xiaotian Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
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Saleh SAB, Abdelwahab KM, Mady AM, Mohamed GA. The impact of achieving a sustained virological response with direct-acting antivirals on serum autotaxin levels in chronic hepatitis C patients. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00060-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/11/2022] Open
Abstract
Abstract
Background
Autotaxin (ATX) is an emerging biomarker for liver fibrosis. Achievement of sustained virological response (SVR) by direct-acting antivirals (DAAs) results in hepatic fibrosis regression in chronic hepatitis C (CHC) patients. In this context, the clinical implications of ATX have not yet been well-defined. In this study, we aimed to assess the impact of achieving SVR with DAA therapy on serum ATX levels and whether these levels can reflect the regression of hepatic fibrosis in CHC patients. We evaluated serum ATX levels at baseline and 12 weeks post-DAA therapy in 48 CHC patients. We compared ATX with FIB4 score and AST-to-Platelet Ratio Index (APRI) as regards the detection of grade F3–4 fibrosis.
Results
Serum ATX levels were significantly declined in 47 patients after the achievement of SVR12 (p < 0.001). The diagnostic ability of ATX for the detection of grade F3–4 fibrosis was inferior to FIB4 and APRI scores at baseline and SVR12.
Conclusion
Achievement of SVR with DAA therapy causes a significant decline in serum autotaxin concentrations, suggesting early regression of hepatic fibrosis in CHC patients. However, its diagnostic capability for routine patient monitoring and follow-up is still under debate.
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Kim SJ, Howe C, Mitchell J, Choo J, Powers A, Oikonomopoulos A, Pothoulakis C, Hommes DW, Im E, Rhee SH. Autotaxin loss accelerates intestinal inflammation by suppressing TLR4-mediated immune responses. EMBO Rep 2020; 21:e49332. [PMID: 32875703 DOI: 10.15252/embr.201949332] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/23/2019] [Revised: 07/20/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022] Open
Abstract
Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl-phosphorylcholine into lysophosphatidic acid and sphingosine 1-phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage-restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll-like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4-mediated responses in macrophages. Accordingly, TLR4-induced innate immune functions, including phagocytosis and iNOS expression, are attenuated in Atx-deficient macrophages. Consequently, Atx-/- mice exhibit a higher bacterial prevalence in the intestinal mucosa compared to controls. When combined with global Il10-/- mice, which show spontaneous colitis due to the translocation of luminal commensal microbes into the mucosa, myeloid cell lineage-restricted Atx knockout accelerates colitis development compared to control littermates. Collectively, our data reveal that Atx deficiency compromises innate immune responses, thereby promoting microbe-associated gut inflammation.
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Affiliation(s)
- Su Jin Kim
- Department of Biological Sciences, Oakland University, Rochester, MI, USA.,College of Pharmacy, Pusan National University, Busan, Korea
| | - Cody Howe
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
| | - Jonathon Mitchell
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
| | - Jieun Choo
- College of Pharmacy, Pusan National University, Busan, Korea
| | - Alexandra Powers
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
| | - Angelos Oikonomopoulos
- Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Charalabos Pothoulakis
- Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Daniel W Hommes
- Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, Korea
| | - Sang Hoon Rhee
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
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Ng SSW, Jang GH, Kurland IJ, Qiu Y, Guha C, Dawson LA. Plasma metabolomic profiles in liver cancer patients following stereotactic body radiotherapy. EBioMedicine 2020; 59:102973. [PMID: 32891936 PMCID: PMC7484529 DOI: 10.1016/j.ebiom.2020.102973] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/01/2020] [Revised: 08/02/2020] [Accepted: 08/10/2020] [Indexed: 12/22/2022] Open
Abstract
Background Stereotactic body radiotherapy (SBRT) is an effective treatment for hepatocellular carcinoma (HCC). This study sought to identify differentially expressed plasma metabolites in HCC patients at baseline and early during SBRT, and to explore if changes in these metabolites early during SBRT may serve as biomarkers for radiation-induced liver injury and/or tumour response. Methods Forty-seven HCC patients were treated with SBRT on previously published prospective trials. Plasma samples were collected at baseline and after one to two fractions of SBRT, and analysed by GC/MS and LC/MS for untargeted and targeted metabolomics profiling, respectively. Findings Sixty-nine metabolites at baseline and 62 metabolites after one to two fractions of SBRT were differentially expressed, and strongly separated the Child Pugh (CP) B from the CP A HCC patients. These metabolites are associated with oxidative stress and alterations in hepatic cellular metabolism. Differential upregulation of serine, alanine, taurine, and lipid metabolites early during SBRT from baseline was noted in the HCC patients who demonstrated the greatest increase in CP scores at three months post SBRT, suggesting that high protein and lipid turnover early during SBRT may portend increased clinical liver toxicity. Twenty annotated metabolites including fatty acids, glycerophospholipids, and acylcarnitines were differentially upregulated early during SBRT from baseline and separated patients with complete/partial response from those with stable disease at three months post SBRT. Interpretation Dysregulation of amino acid and lipid metabolism detected early during SBRT are associated with subsequent clinical liver injury and tumour response in HCC.
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Affiliation(s)
- Sylvia S W Ng
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada
| | - Gun Ho Jang
- Division of Bioinformatics, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Irwin J Kurland
- Stable Isotope and Metabolomics Core Facility, Centre for Medical Counter-Measures Against Radiation, Albert Einstein College of Medicine, Bronx, NY USA
| | - Yunping Qiu
- Stable Isotope and Metabolomics Core Facility, Centre for Medical Counter-Measures Against Radiation, Albert Einstein College of Medicine, Bronx, NY USA
| | - Chandan Guha
- Stable Isotope and Metabolomics Core Facility, Centre for Medical Counter-Measures Against Radiation, Albert Einstein College of Medicine, Bronx, NY USA
| | - Laura A Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
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Tang X, Brindley DN. Lipid Phosphate Phosphatases and Cancer. Biomolecules 2020; 10:biom10091263. [PMID: 32887262 PMCID: PMC7564803 DOI: 10.3390/biom10091263] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/12/2020] [Revised: 08/28/2020] [Accepted: 08/30/2020] [Indexed: 12/22/2022] Open
Abstract
Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1–3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers.
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Affiliation(s)
- Xiaoyun Tang
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - David N. Brindley
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Correspondence:
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Salgüero S, Rojo D, Berenguer J, González-García J, Fernández-Rodríguez A, Brochado-Kith O, Díez C, Hontañon V, Virseda-Berdices A, Martínez J, Ibañez-Samaniego L, Llop-Herrera E, Barbas C, Resino S, Jiménez-Sousa MA. Plasma metabolomic fingerprint of advanced cirrhosis stages among HIV/HCV-coinfected and HCV-monoinfected patients. Liver Int 2020; 40:2215-2227. [PMID: 32593189 DOI: 10.1111/liv.14580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/26/2019] [Revised: 04/24/2020] [Accepted: 06/16/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and cirrhosis induce metabolic disorders. Here, we aimed to evaluate the association of plasma metabolites with Child-Turcotte-Pugh (CTP) score and hepatic decompensation in HIV/HCV-coinfected and HCV-monoinfected patients with advanced cirrhosis. METHODS A cross-sectional study was carried out in 62 HIV/HCV-coinfected and 28 HCV-monoinfected patients. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by partial least squares discriminant analysis (PLS-DA) and generalized linear model (GLM) with binomial distribution (to analyse HIV coinfection, high alcohol intake, treatment with statins, previous HCV therapy failure and decompensation) and ordinal logistic regression (OLR) models to analyse different stages of cirrhosis (CTP score). RESULTS The statistical analysis identified plasma metabolites associated with HIV coinfection, high alcohol intake, CTP score and hepatic decompensation. Overall, fatty acids, bile acids, aromatic and sulphur amino acids, butyrate derivatives, oxidized phospholipids, energy-related metabolites and bacterial fermentation-related metabolites were increased in more advanced cirrhosis stages; while lysophosphatidylcholines and lysophosphatidylethanolamines, branched-chain amino acids (BCAA) and metabolites of tricarboxylic acid cycle, among others, were decreased in more advanced cirrhosis. Most of the significant metabolites displayed a similar trend after stratifying for HIV/HCV- and HCV-infected patients. Glycolic acid, LPC (16:0) and taurocholic acid had high accuracy for discriminating patients according to decompensated cirrhosis (CTP ≥ 7). CONCLUSION Altered plasma metabolomic profile was associated with advanced stages of cirrhosis in HIV/HCV-coinfected and HCV-monoinfected patients.
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Affiliation(s)
- Sergio Salgüero
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.,Unidad de Análisis Clínicos. Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | - David Rojo
- Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Juan Berenguer
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario "Gregorio Marañón", Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Juan González-García
- Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain.,Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Oscar Brochado-Kith
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Cristina Díez
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario "Gregorio Marañón", Madrid, Spain.,Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Victor Hontañon
- Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain.,Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain
| | - Ana Virseda-Berdices
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Javier Martínez
- Servicio de Aparato Digestivo, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Luis Ibañez-Samaniego
- Servicio de Aparato Digestivo, Hospital General Universitario "Gregorio Marañón", Madrid, Spain
| | - Elba Llop-Herrera
- Departamento de Gastroenterología, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
| | - Coral Barbas
- Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - María A Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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Sato K. Plasma Lipid Profiling of Three Types of Drug-Induced Liver Injury in Japanese Patients: A Preliminary Study. Metabolites 2020; 10:metabo10090355. [PMID: 32878279 PMCID: PMC7569965 DOI: 10.3390/metabo10090355] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/16/2020] [Revised: 08/26/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
Drug-induced liver injury (DILI) is a major adverse event caused by drug treatment, which can be categorized into three types: hepatocellular, mixed, and cholestatic. Although nearly every class of drugs can cause DILI, an overall understanding of lipid profiles in DILI patients is lacking. We used lipidomics to analyze the plasma lipid profiles of patients to understand their hepatic pathophysiology and identify DILI biomarkers. We identified 463 lipids and compared their levels between the acute and recovery phases of the three types of DILI patients. Mixed and cholestatic types demonstrated specific plasma lipid alterations between the phases, but the hepatocellular type did not. Moreover, as specific indicators of mixed-type DILI, levels of several ceramides increased in the acute phase, while those of arachidonic acid-containing ether-linked phosphoglycerolipids decreased. In contrast, as specific indicators of cholestatic-type DILI, levels of palmitic acid-containing saturated or monounsaturated phosphatidylcholines increased in the acute phase, while those of arachidonic acid- or docosahexaenoic acid-containing ether-linked phosphoglycerolipids and phosphatidylinositols decreased. We also identified lipids with a relatively high capacity to discriminate the acute phase from the recovery phase and healthy subjects. These findings may help with understanding the pathophysiology of different DILI types and identify candidate biomarkers.
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Regulation of Tumor Immunity by Lysophosphatidic Acid. Cancers (Basel) 2020; 12:cancers12051202. [PMID: 32397679 PMCID: PMC7281403 DOI: 10.3390/cancers12051202] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/24/2020] [Revised: 05/08/2020] [Accepted: 05/09/2020] [Indexed: 12/16/2022] Open
Abstract
The tumor microenvironment (TME) may be best conceptualized as an ecosystem comprised of cancer cells interacting with a multitude of stromal components such as the extracellular matrix (ECM), blood and lymphatic networks, fibroblasts, adipocytes, and cells of the immune system. At the center of this crosstalk between cancer cells and their TME is the bioactive lipid lysophosphatidic acid (LPA). High levels of LPA and the enzyme generating it, termed autotaxin (ATX), are present in many cancers. It is also well documented that LPA drives tumor progression by promoting angiogenesis, proliferation, survival, invasion and metastasis. One of the hallmarks of cancer is the ability to modulate and escape immune detection and eradication. Despite the profound role of LPA in regulating immune functions and inflammation, its role in the context of tumor immunity has not received much attention until recently where emerging studies highlight that this signaling axis may be a means that cancer cells adopt to evade immune detection and eradication. The present review aims to look at the immunomodulatory actions of LPA in baseline immunity to provide a broad understanding of the subject with a special emphasis on LPA and cancer immunity, highlighting the latest progress in this area of research.
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Plastira I, Bernhart E, Joshi L, Koyani CN, Strohmaier H, Reicher H, Malle E, Sattler W. MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia. J Neuroinflammation 2020; 17:127. [PMID: 32326963 PMCID: PMC7178949 DOI: 10.1186/s12974-020-01809-1] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/13/2019] [Accepted: 04/08/2020] [Indexed: 12/12/2022] Open
Abstract
Background In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia. Methods In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACS-sorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia. Results Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and -3, p65, and c-Jun) and secretion of IL-6 and TNFα. All three inhibitors decreased LPA-mediated secretion of IL-1β, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media. Conclusion In the present study, we show that systemic inflammation induces aberrant ATX/LPA/LPAR homeostasis in the murine brain. LPA-mediated polarization of primary microglia via MAPK-dependent pathways induces features reminiscent of a neurotoxic phenotype.
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Affiliation(s)
- Ioanna Plastira
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/6, 8010, Graz, Austria
| | - Eva Bernhart
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/6, 8010, Graz, Austria
| | - Lisha Joshi
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/6, 8010, Graz, Austria
| | - Chintan N Koyani
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/6, 8010, Graz, Austria.,Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Heimo Strohmaier
- Center for Medical Research, Medical University of Graz, Graz, Austria
| | - Helga Reicher
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/6, 8010, Graz, Austria
| | - Ernst Malle
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/6, 8010, Graz, Austria
| | - Wolfgang Sattler
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/6, 8010, Graz, Austria. .,Center for Explorative Lipidomics, BioTechMed, Graz, Austria.
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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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Buechler C, Aslanidis C. Role of lipids in pathophysiology, diagnosis and therapy of hepatocellular carcinoma. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158658. [PMID: 32058031 DOI: 10.1016/j.bbalip.2020.158658] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/03/2019] [Revised: 12/05/2019] [Accepted: 02/06/2020] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive and widespread cancer. Patients with liver cirrhosis of different aetiologies are at a risk to develop HCC. It is important to know that in approximately 20% of cases primary liver tumors arise in a non-cirrhotic liver. Lipid metabolism is variable in patients with chronic liver diseases, and lipid metabolites involved therein do play a role in the development of HCC. Of note, lipid composition of carcinogenic tissues differs from non-affected liver tissues. High cholesterol and low ceramide levels in the tumors protect the cells from oxidative stress and apoptosis, and do also promote cell proliferation. So far, detailed characterization of the mechanisms by which lipids enable the development of HCC has received little attention. Evaluation of the complex roles of lipids in HCC is needed to better understand the pathophysiology of HCC, the later being of paramount importance for the development of urgently needed therapeutic interventions. Disturbed hepatic lipid homeostasis has systemic consequences and lipid species may emerge as promising biomarkers for early diagnosis of HCC. The challenge is to distinguish lipids specifically related to HCC from changes simply related to the underlying liver disease. This review article discusses aberrant lipid metabolism in patients with HCC.
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Affiliation(s)
- Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
| | - Charalampos Aslanidis
- Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
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40
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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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Argaud D, Boulanger MC, Chignon A, Mkannez G, Mathieu P. Enhancer-mediated enrichment of interacting JMJD3-DDX21 to ENPP2 locus prevents R-loop formation and promotes transcription. Nucleic Acids Res 2019; 47:8424-8438. [PMID: 31251802 PMCID: PMC6895255 DOI: 10.1093/nar/gkz560] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/13/2018] [Revised: 06/17/2019] [Accepted: 06/25/2019] [Indexed: 12/11/2022] Open
Abstract
ENPP2, which encodes for the enzyme autotaxin (ATX), is overexpressed during chronic inflammatory diseases and various cancers. However, the molecular mechanism involved in the ENPP2 transcription remains elusive. Here, in HEK 293T cells, we demonstrated that lipopolysaccharide (LPS) increased the transcription process at ENPP2 locus through a NF-кB pathway and a reduction of H3K27me3 level, a histone repressive mark, by the demethylase UTX. Simultaneously, the H3K27me3 demethylase JMJD3/KDM6B was recruited to the transcription start site (TSS), within the gene body and controlled the expression of ENPP2 in a non-enzymatic manner. Mass spectrometry data revealed a novel interaction for JMJD3 with DDX21, a RNA helicase that unwinds R-loops created by nascent transcript and DNA template. Upon LPS treatment, JMJD3 is necessary for DDX21 recruitment at ENPP2 locus allowing the resolution of aberrant R-loops. CRISPR-Cas9-mediated deletion of a distant-acting enhancer decreased the expression of ENPP2 and lowered the recruitment of JMJD3–DDX21 complex at TSS and its progression through the gene body. Taken together, these findings revealed that enhancer-mediated enrichment of novel JMJD3–DDX21 interaction at ENPP2 locus is necessary for nascent transcript synthesis via the resolution of aberrant R-loops formation in response to inflammatory stimulus.
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Affiliation(s)
- Deborah Argaud
- Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec G1V-4G5, Canada
| | - Marie-Chloé Boulanger
- Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec G1V-4G5, Canada
| | - Arnaud Chignon
- Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec G1V-4G5, Canada
| | - Ghada Mkannez
- Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec G1V-4G5, Canada
| | - Patrick Mathieu
- Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec G1V-4G5, Canada
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Elevated Autotaxin and LPA Levels During Chronic Viral Hepatitis and Hepatocellular Carcinoma Associate with Systemic Immune Activation. Cancers (Basel) 2019; 11:cancers11121867. [PMID: 31769428 PMCID: PMC6966516 DOI: 10.3390/cancers11121867] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/14/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 12/16/2022] Open
Abstract
Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid (LPA) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC).
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Deregulated Lysophosphatidic Acid Metabolism and Signaling in Liver Cancer. Cancers (Basel) 2019; 11:cancers11111626. [PMID: 31652837 PMCID: PMC6893780 DOI: 10.3390/cancers11111626] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/26/2019] [Revised: 10/18/2019] [Accepted: 10/20/2019] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.
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Flammier S, Peyruchaud O, Bourguillault F, Duboeuf F, Davignon JL, Norman DD, Isaac S, Marotte H, Tigyi G, Machuca-Gayet I, Coury F. Osteoclast-Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss. Arthritis Rheumatol 2019; 71:1801-1811. [PMID: 31162832 DOI: 10.1002/art.41005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/23/2018] [Accepted: 05/29/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVE The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown. METHODS ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXC tsk ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF+/- ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays. RESULTS OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/- mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties. CONCLUSION Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.
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Affiliation(s)
- Sacha Flammier
- INSERM UMR 1033 LYOS and University of Lyon I, Lyon, France
| | | | | | | | - Jean-Luc Davignon
- University of Paul Sabatier Toulouse III, INSERM-CNRS U1043, CPTP, CHU Purpan, and Pierre Paul Riquet Hospital, Toulouse, France
| | - Derek D Norman
- University of Tennessee Health Sciences Center, Memphis, Tennessee
| | | | - Hubert Marotte
- SAINBIOSE, INSERM, U1059, LBTO, University of Lyon, and University Hospital of St. Étienne, St. Étienne, France
| | - Gabor Tigyi
- University of Tennessee Health Sciences Center, Memphis, Tennessee
| | | | - Fabienne Coury
- INSERM UMR 1033 LYOS and University of Lyon I, Lyon, France, and Lyon Sud Hospital, Pierre-Bénite, France
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CPAP promotes angiogenesis and metastasis by enhancing STAT3 activity. Cell Death Differ 2019; 27:1259-1273. [PMID: 31511651 PMCID: PMC7206147 DOI: 10.1038/s41418-019-0413-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/13/2019] [Revised: 08/09/2019] [Accepted: 08/16/2019] [Indexed: 12/12/2022] Open
Abstract
Centrosomal P4.1-associated protein (CPAP) is overexpressed in hepatocellular carcinoma (HCC) and positively correlated with recurrence and vascular invasion. Here, we found that CPAP plays an important role in HCC malignancies. Functional characterization indicated that CPAP overexpression increases tumor growth, angiogenesis, and metastasis ex vivo and in vivo. In addition, overexpressed CPAP contributes to sorafenib resistance. Mechanical investigation showed that the expression level of CPAP is positively correlated with activated STAT3 in HCC. CPAP acts as a transcriptional coactivator of STAT3 by directly binding with STAT3. Interrupting the interaction between CPAP and STAT3 attenuates STAT3-mediated tumor growth and angiogenesis. Overexpression of CPAP upregulates several STAT3 target genes such as IL-8 and CD44 that are involved in angiogenesis, and CPAP mRNA expression is positively correlated with the levels of both mRNAs in HCC. Knocked-down expression of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion abilities. IL-6/STAT3-mediated angiogenesis is significantly increased by CPAP overexpression and can be blocked by decreased expression of IL-8. Our findings not only shed light on the importance of CPAP in HCC malignancies, but also provide potential therapeutic strategies for inhibiting the angiogenesis pathway and treating metastatic HCC.
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Magkrioti C, Galaris A, Kanellopoulou P, Stylianaki EA, Kaffe E, Aidinis V. Autotaxin and chronic inflammatory diseases. J Autoimmun 2019; 104:102327. [PMID: 31471142 DOI: 10.1016/j.jaut.2019.102327] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/17/2019] [Accepted: 08/17/2019] [Indexed: 12/18/2022]
Abstract
Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids including blood. ATX catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a growth factor-like, signaling phospholipid. LPA exerts pleiotropic effects mediated by its G-protein-coupled receptors that are widely expressed and exhibit overlapping specificities. Although ATX also possesses matricellular properties, the majority of ATX reported functions in adulthood are thought to be mediated through the extracellular production of LPA. ATX-mediated LPA synthesis is likely localized at the cell surface through the possible interaction of ATX with integrins or other molecules, while LPA levels are further controlled by a group of membrane-associated lipid-phosphate phosphatases. ATX expression was shown to be necessary for embryonic development, and ATX deficient embryos exhibit defective vascular homeostasis and aberrant neuronal system development. In adult life, ATX is highly expressed in the adipose tissue and has been implicated in diet-induced obesity and glucose homeostasis with multiple implications in metabolic disorders. Additionally, LPA has been shown to affect multiple cell types, including stromal and immune cells in various ways. Therefore, LPA participates in many processes that are intricately involved in the pathogenesis of different chronic inflammatory diseases such as vascular homeostasis, skeletal and stromal remodeling, lymphocyte trafficking and immune regulation. Accordingly, increased ATX and LPA levels have been detected, locally and/or systemically, in patients with chronic inflammatory diseases, most notably idiopathic pulmonary fibrosis (IPF), chronic liver diseases, and rheumatoid arthritis. Genetic and pharmacological studies in mice have confirmed a pathogenetic role for ATX expression and LPA signaling in chronic inflammatory diseases, and provided the proof of principle for therapeutic interventions, as exemplified by the ongoing clinical trials for IPF.
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Affiliation(s)
| | - Apostolos Galaris
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece
| | | | | | - Eleanna Kaffe
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece
| | - Vassilis Aidinis
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece.
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Briard E, Joshi AD, Shanmukhappa S, Ilovich O, Auberson YP. [
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F]PRIMATX, a New Positron Emission Tomography Tracer for Imaging of Autotaxin in Lung Tissue and Tumor‐Bearing Mice. ChemMedChem 2019; 14:1493-1502. [DOI: 10.1002/cmdc.201900297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/17/2019] [Indexed: 11/08/2022]
Affiliation(s)
- Emmanuelle Briard
- Global Discovery ChemistryNovartis Institutes for BioMedical ResearchNovartis Pharma AG Klybeckstrasse 141 4057 Basel Switzerland
| | - Aniket D. Joshi
- Clinical and Translational ImagingNovartis Pharmaceuticals 45 Sidney Street, 1203K Cambridge MA 01239 USA
| | - Shiva Shanmukhappa
- Discovery and Investigative Safety, Preclincial SafetyNovartis Institutes for BioMedical Research 250 Massachusetts Avenue Cambridge MA 01239 USA
| | - Ohad Ilovich
- inviCRO, LLC 27 Dry Dock Avenue, 7th Floor West Boston MA 02210 USA
| | - Yves P. Auberson
- Global Discovery ChemistryNovartis Institutes for BioMedical ResearchNovartis Pharma AG Klybeckstrasse 141 4057 Basel Switzerland
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48
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Pleotropic Roles of Autotaxin in the Nervous System Present Opportunities for the Development of Novel Therapeutics for Neurological Diseases. Mol Neurobiol 2019; 57:372-392. [PMID: 31364025 DOI: 10.1007/s12035-019-01719-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/16/2019] [Accepted: 07/23/2019] [Indexed: 12/23/2022]
Abstract
Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.
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Wang Y, Lyu L, Zhang X, Zhang J. Autotaxin is a novel target of microRNA-101-3p. FEBS Open Bio 2019; 9:707-716. [PMID: 30984544 PMCID: PMC6443858 DOI: 10.1002/2211-5463.12608] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/21/2018] [Revised: 01/26/2019] [Accepted: 02/04/2019] [Indexed: 12/13/2022] Open
Abstract
Autotaxin (ATX), a vital enzyme that generates lysophosphatidic acid (LPA), affects many biological processes, including tumorigenesis, via the ATX–LPA axis. In this study, we demonstrate that microRNA‐101‐3p (miR‐101‐3p), a well‐known tumor suppressor, downregulates ATX expression at the posttranscriptional level. We found that miR‐101‐3p inhibits ATX regulation by directly targeting a conserved sequence in the ATX mRNA 3′UTR. Moreover, we observed an inverse correlation between ATX and miR‐101‐3p levels in various types of cancer cells. ATX is highly expressed in several human cancers. Here, we verified that ATX expression is significantly inhibited by miR‐101‐3p in U87 and HCT116 cells. ATX downregulation contributed to the suppression of migration, invasion, and proliferation mediated by miR‐101‐3p; furthermore, the tumor‐suppressing activity of miR‐101‐3p was partially reduced by the addition of LPA in U87 cells. Our data suggest that ATX is a novel target of miR‐101‐3p.
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Affiliation(s)
- Yuqin Wang
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
| | - Lin Lyu
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
| | - Xiaotian Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
| | - Junjie Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology Ministry of Education Institute of Cell Biology College of Life Sciences Beijing Normal University China
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50
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Zhang Q, Xu H, Liu R, Gao P, Yang X, Jin W, Zhang Y, Bi K, Li Q. A Novel Strategy for Targeted Lipidomics Based on LC-Tandem-MS Parameters Prediction, Quantification, and Multiple Statistical Data Mining: Evaluation of Lysophosphatidylcholines as Potential Cancer Biomarkers. Anal Chem 2019; 91:3389-3396. [DOI: 10.1021/acs.analchem.8b04715] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/29/2022]
Affiliation(s)
- Qian Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Huarong Xu
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Ran Liu
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Peng Gao
- Metabolomics Core Facility of RHLCCC, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Xiao Yang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Wei Jin
- Urumqi Traditional Chinese Medicine Hospital, 590 Youhao South Road, Urumqi 830000, China
| | - Yiwen Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Kaishun Bi
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
| | - Qing Li
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
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