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Martin RE, Satz AL, Kuratli C, Hunziker D, Mattei P, Hert J, Ullmer C, Rudolph MG, Alker AM, Hochstrasser R, Marx A, Binder M, Müller S. Optimization of a DNA encoded library derived autotaxin inhibitor hit to a potent in vivo LPA lowering quinazolinone compound with a non‑zinc binding mode. Bioorg Med Chem Lett 2025; 123:130221. [PMID: 40194669 DOI: 10.1016/j.bmcl.2025.130221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/27/2025] [Accepted: 04/03/2025] [Indexed: 04/09/2025]
Abstract
In recent years, lysophospholipase autotaxin (ATX) has emerged as an attractive target for treating a variety of human diseases, including inflammation, neurodegeneration, angiogenesis, cancer, ocular and fibrotic diseases, among others. Starting with the quinazolinone hit structure 1, which emerged from a DNA-encoded library screen, the potent, non-Zn2+ binding ATX inhibitor 31 with good overall physicochemical properties has been developed. This compound demonstrated a sustained reduction of lysophosphatidic acid (LPA) in an in vivo rat experiment, qualifying it as a proof-of-concept compound for further mechanistic studies.
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Affiliation(s)
- Rainer E Martin
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
| | - Alexander L Satz
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Christoph Kuratli
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Daniel Hunziker
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Patrizio Mattei
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Jérôme Hert
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Christoph Ullmer
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Markus G Rudolph
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - André M Alker
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Remo Hochstrasser
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Andreas Marx
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Martin Binder
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Stephan Müller
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
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Rai P, Clark CJ, Kardam V, Womack CB, Thammathong J, Norman DD, Tigyi GJ, Bicker K, Weissmiller AM, Dubey KD, Banerjee S. Structure-Based Discovery of MolPort-137: A Novel Autotaxin Inhibitor That Improves Paclitaxel Efficacy. Int J Mol Sci 2025; 26:597. [PMID: 39859312 PMCID: PMC11765394 DOI: 10.3390/ijms26020597] [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] [Scholar Register] [Received: 12/19/2024] [Revised: 01/08/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The autotaxin-lysophosphatidic acid receptor (ATX-LPAR) signaling axis is pivotal in various clinical conditions, including cancer and autoimmune disorders. This axis promotes tumorigenicity by interacting with the tumor microenvironment, facilitating metastasis, and conceding antitumor immunity, thereby fostering resistance to conventional cancer therapies. Recent studies highlight the promise of ATX/LPAR inhibitors in combination with conventional chemotherapeutic drugs to overcome some forms of this resistance, representing a novel therapeutic strategy. In the current study, we employed structure-based virtual screening, integrating pharmacophore modeling and molecular docking, to identify MolPort-137 as a novel ATX inhibitor with an IC50 value of 1.6 ± 0.2 μM in an autotaxin enzyme inhibition assay. Molecular dynamics simulations and binding free energy calculations elucidated the binding mode of MolPort-137 and its critical amino acid interactions. Remarkably, MolPort-137 exhibited no cytotoxicity as a single agent but enhanced the effectiveness of paclitaxel in 4T1 murine breast carcinoma cells and resensitized taxol-resistant cells to paclitaxel treatment, which highlights its potential in combination therapy.
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Affiliation(s)
- Prateek Rai
- Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA; (P.R.); (C.J.C.); (K.B.); (A.M.W.)
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA;
| | - Christopher J. Clark
- Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA; (P.R.); (C.J.C.); (K.B.); (A.M.W.)
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA;
| | - Vandana Kardam
- Department of Chemistry, Shiv Nadar Institution of Eminence, Delhi 201314, India;
| | - Carl B. Womack
- Department of Biology, Middle Tennessee State University, Murfreesboro, TN 37132, USA;
| | - Joshua Thammathong
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA;
| | - Derek D. Norman
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 37132, USA; (D.D.N.); (G.J.T.)
| | - Gábor J. Tigyi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 37132, USA; (D.D.N.); (G.J.T.)
| | - Kevin Bicker
- Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA; (P.R.); (C.J.C.); (K.B.); (A.M.W.)
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA;
| | - April M. Weissmiller
- Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA; (P.R.); (C.J.C.); (K.B.); (A.M.W.)
- Department of Biology, Middle Tennessee State University, Murfreesboro, TN 37132, USA;
| | | | - Souvik Banerjee
- Molecular Biosciences, Middle Tennessee State University, Murfreesboro, TN 37132, USA; (P.R.); (C.J.C.); (K.B.); (A.M.W.)
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA;
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Lampiasi N. Macrophage Polarization: Learning to Manage It 3.0. Int J Mol Sci 2025; 26:311. [PMID: 39796166 PMCID: PMC11719942 DOI: 10.3390/ijms26010311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025] Open
Abstract
Macrophages are cells of the innate immune system with very peculiar characteristics, so plastic that they respond rapidly to environmental changes by assuming different and sometimes contrasting functions, such as initiating a physiological inflammatory response or interrupting it and repairing damaged tissues [...].
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Affiliation(s)
- Nadia Lampiasi
- Consiglio Nazionale delle Ricerche, Istituto per la Ricerca e l'Innovazione Biomedica, Via Ugo La Malfa 153, 90146 Palermo, Italy
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4
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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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Benesch MG, Wu R, Rog CJ, Brindley DN, Ishikawa T, Takabe K. Insights into autotaxin- and lysophosphatidate-mediated signaling in the pancreatic ductal adenocarcinoma tumor microenvironment: a survey of pathway gene expression. Am J Cancer Res 2024; 14:4004-4027. [PMID: 39267662 PMCID: PMC11387861 DOI: 10.62347/kqnw1871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 08/07/2024] [Indexed: 09/15/2024] Open
Abstract
Lysophosphatidate (LPA)-mediated signaling is a vital component of physiological wound healing, but the pathway is subverted to mediate chronic inflammatory signaling in many pathologies, including cancers. LPA, as an extracellular signaling molecule, is produced by the enzyme autotaxin (ATX, gene name ENPP2) and signals through six LPA receptors (LPARs). Its signaling is terminated by turnover via the ecto-activity of three lipid phosphate phosphatases (LPPs, gene names PLPP1-3). Many pharmacological developments against the LPA-signaling axis are underway, primarily against ATX. An ATX inhibitor against pancreatic ductal adenocarcinoma (PDAC), a very aggressive disease with limited systemic therapeutic options, is currently in clinical trials, and represents the first in-class drug against LPA signaling in cancers. In the present study, we surveyed the expression of ATX, LPARs, and LPPs in human PDACs and their clinical outcomes in two large independent cohorts, the Cancer Genome Atlas (TCGA) and GSE21501. Correlation among gene expressions, biological function and the cell composition of the tumor microenvironment were analysed using gene set enrichment analysis and cell cyber-sorting with xCell. ENPP2, LPAR1, LPAR4, LPAR5, LPAR6, PLPP1, and PLPP2 were significantly elevated in PDACs compared to normal pancreatic tissue, whereas LPAR2, LPAR3, and PLPP3 where downregulated (all P≤0.003). Only ENPP2 demonstrated survival differences, with overall survival favoring ENPP2-high patients (hazard ration 0.5-0.9). ENPP2 was also the only gene with enriched gene patterns for inflammatory and tissue repair gene sets. Epithelial (cancer) cells had increased LPAR2, LPAR5 and PLPP2 expression, and decreased ENPP2, LPAR1, PLPP1, and PLPP3 gene expression (all P<0.02). Tumor fibroblasts had increased ENPP2, LPAR2, LPAR4, PLPP1, and PLPP3 expression and decreased LPAR2, LPAR5, and PLPP2 expression in both cohorts (all P≤0.01). Immune cell populations were not well correlated to gene expression in PDACs, but across both cohorts, cytolytic scores were increased in high-expressing ENPP2, LPAR1, LPAR6, PLPP1, and PLPP3 tumors (P<0.01). Overall, in PDACs, ENPP2 may switch from an anti-to-pro tumor promoting gene with disease progression. LPAR2 and PLPP2 inhibition are also predicted to have potential therapeutic utility. Future multi-omics investigations are necessarily to validate which LPA signaling components are high-value candidates for pharmacological manipulation in PDAC treatment.
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Affiliation(s)
- Matthew Gk Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University Tokyo 160-8402, Japan
| | - Colin J Rog
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA
| | - David N Brindley
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta Edmonton, Alberta T6G 2S7, Canada
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University Tokyo 160-8402, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University Tokyo 160-8402, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine Yokohama 236-0004, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine Fukushima 960-1295, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New York Buffalo, New York 14263, USA
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Birgbauer E. Lysophospholipid receptors in neurodegeneration and neuroprotection. EXPLORATION OF NEUROPROTECTIVE THERAPY 2024; 4:349-365. [PMID: 39247084 PMCID: PMC11379401 DOI: 10.37349/ent.2024.00088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 08/11/2024] [Indexed: 09/10/2024]
Abstract
The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of major medical need. One critical aspect of the CNS is its lack of regeneration, such that damage is often permanent. The damage often leads to neurodegeneration, and so strategies for neuroprotection could lead to major medical advances. The G protein-coupled receptor (GPCR) family is one of the major receptor classes, and they have been successfully targeted clinically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors in neurodegeneration and potential roles in neuroprotection. Much of our understanding of the role of S1P receptors has been through pharmacological tools. One such tool, fingolimod (also known as FTY720), which is a S1P receptor agonist but a functional antagonist in the immune system, is clinically efficacious in multiple sclerosis by producing a lymphopenia to reduce autoimmune attacks; however, there is evidence that fingolimod is also neuroprotective. Furthermore, fingolimod is neuroprotective in many other neuropathologies, including stroke, Parkinson's disease, Huntington's disease, Rett syndrome, Alzheimer's disease, and others that are discussed here. LPA receptors also appear to be involved, being upregulated in a variety of neuropathologies. Antagonists or mutations of LPA receptors, especially LPA1, are neuroprotective in a variety of conditions, including cortical development, traumatic brain injury, spinal cord injury, stroke and others discussed here. Finally, LPA receptors may interact with other receptors, including a functional interaction with plasticity related genes.
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Affiliation(s)
- Eric Birgbauer
- Department of Biology, Winthrop University, Rock Hill, SC 29733, USA
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7
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Benesch MG, Tang X, Brindley DN, Takabe K. Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer. World J Oncol 2024; 15:1-13. [PMID: 38274724 PMCID: PMC10807915 DOI: 10.14740/wjon1762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 12/29/2023] [Indexed: 01/27/2024] Open
Abstract
Overcoming and preventing cancer therapy resistance is the most pressing challenge in modern breast cancer management. Consequently, most modern breast cancer research is aimed at understanding and blocking these therapy resistance mechanisms. One increasingly promising therapeutic target is the autotaxin (ATX)-lysophosphatidate (LPA)-lipid phosphate phosphatase (LPP) axis. Extracellular LPA, produced from albumin-bound lysophosphatidylcholine by ATX and degraded by the ecto-activity of the LPPs, is a potent cell-signaling mediator of tumor growth, invasion, angiogenesis, immune evasion, and resistance to cancer treatment modalities. LPA signaling in the post-natal organism has central roles in physiological wound healing, but these mechanisms are subverted to fuel pathogenesis in diseases that arise from chronic inflammatory processes, including cancer. Over the last 10 years, our understanding of the role of LPA signaling in the breast tumor microenvironment has begun to mature. Tumor-promoting inflammation in breast cancer leads to increased ATX production within the tumor microenvironment. This results in increased local concentrations of LPA that are maintained in part by decreased overall cancer cell LPP expression that would otherwise more rapidly break it down. LPA signaling through six G-protein-coupled LPA receptors expressed by cancer cells can then activate virtually every known tumorigenic pathway. Consequently, to target therapy resistance and tumor growth mediated by LPA signaling, multiple inhibitors against the LPA signaling axis are entering clinical trials. In this review, we summarize recent developments in LPA breast cancer biology, and illustrate how these novel therapeutics against the LPA signaling pathway may be excellent adjuncts to extend the efficacy of evolving breast cancer treatments.
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Affiliation(s)
- Matthew G.K. Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Xiaoyun Tang
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - David N. Brindley
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
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Tzenaki N, Xenou L, Goulielmaki E, Tsapara A, Voudouri I, Antoniou A, Valianatos G, Tzardi M, De Bree E, Berdiaki A, Makrigiannakis A, Papakonstanti EA. A combined opposite targeting of p110δ PI3K and RhoA abrogates skin cancer. Commun Biol 2024; 7:26. [PMID: 38182748 PMCID: PMC10770346 DOI: 10.1038/s42003-023-05639-8] [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] [Scholar Register] [Received: 03/07/2023] [Accepted: 11/27/2023] [Indexed: 01/07/2024] Open
Abstract
Malignant melanoma is the most aggressive and deadly skin cancer with an increasing incidence worldwide whereas SCC is the second most common non-melanoma human skin cancer with limited treatment options. Here we show that the development and metastasis of melanoma and SCC cancers can be blocked by a combined opposite targeting of RhoA and p110δ PI3K. We found that a targeted induction of RhoA activity into tumours by deletion of p190RhoGAP-a potent inhibitor of RhoA GTPase-in tumour cells together with adoptive macrophages transfer from δD910A/D910A mice in mice bearing tumours with active RhoA abrogated growth progression of melanoma and SCC tumours. Τhe efficacy of this combined treatment is the same in tumours lacking activating mutations in BRAF and in tumours harbouring the most frequent BRAF(V600E) mutation. Furthermore, the efficiency of this combined treatment is associated with decreased ATX expression in tumour cells and tumour stroma bypassing a positive feedback expression of ATX induced by direct ATX pharmacological inactivation. Together, our findings highlight the importance of targeting cancer cells and macrophages for skin cancer therapy, emerge a reverse link between ATX and RhoA and illustrate the benefit of p110δ PI3K inhibition as a combinatorial regimen for the treatment of skin cancers.
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Affiliation(s)
- Niki Tzenaki
- Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - Lydia Xenou
- Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - Evangelia Goulielmaki
- Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - Anna Tsapara
- Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - Irene Voudouri
- Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - Angelika Antoniou
- Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - George Valianatos
- Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - Maria Tzardi
- Department of Pathology, School of Medicine, University of Crete, University Hospital, Heraklion, Greece
| | - Eelco De Bree
- Department of Surgical Oncology, School of Medicine, University of Crete, University Hospital, Heraklion, Greece
| | - Aikaterini Berdiaki
- Department of Obstetrics and Gynaecology, School of Medicine, University of Crete, University Hospital, Heraklion, Greece
| | - Antonios Makrigiannakis
- Department of Obstetrics and Gynaecology, School of Medicine, University of Crete, University Hospital, Heraklion, Greece
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Jiang S, Yang H, Li M. Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases. Int J Mol Sci 2023; 24:12524. [PMID: 37569902 PMCID: PMC10419859 DOI: 10.3390/ijms241512524] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies.
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Affiliation(s)
- Shufan Jiang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Huili Yang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
| | - Mingqing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
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Sepehrinezhad A, Shahbazi A, Joghataei MT, Larsen FS, Sahab Negah S. Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut-liver-brain axis: an experimental and bioinformatic study. Cell Death Dis 2023; 14:490. [PMID: 37528089 PMCID: PMC10394058 DOI: 10.1038/s41419-023-06022-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/19/2023] [Accepted: 07/26/2023] [Indexed: 08/03/2023]
Abstract
There is accumulating evidence that the circulatory levels of autotaxin (ATX) and lysophosphatidic acid (LPA) are increased in patients with severe liver disease. However, the potential role of the ATX-LPA axis in hepatic encephalopathy (HE) remains unclear. Our study aimed to investigate the role of the ATX-LPA signaling pathway in mice with thioacetamide (TAA) induced acute HE. To show the role of the ATX-LPA axis in the context of HE, we first measured the involvement of ATX-LPA in the pathogenesis of TAA-induced acute HE. Then, we compared the potential effects of ATX inhibitor (HA130) on astrocyte responses at in vitro and gut-liver-brain axis at in vivo levels. The inflammatory chemokine (C-C motif) ligand 3 was significantly increased in the hyperammonemic condition and could be prevented by ATX inhibition in astrocytes at in vitro level. Further statistical tests revealed that plasma and tissue pro-inflammatory cytokines were inhibited by HA130 in mice. Furthermore, the stage of HE was significantly improved by HA130. The most surprising result was that HA130 alleviated immune infiltrating cells in the liver and intestine and decreased mucus-secreting cells in the intestine. Further analysis showed that the levels of liver enzymes in serum were significantly decreased in response to ATX inhibition. Surprisingly, our data indicated that HA130 could recover permeabilization of the blood-brain barrier, neuroinflammation, and recognition memory. Besides that, we found that the changes of Interleukin-1 (IL-1) and aquaporin-4 (AQP4) in HE might have a connection with the glymphatic system based on bioinformatics analyses. Taken together, our data showed that the ATX-LPA axis contributes to the pathogenesis of HE and that inhibition of ATX improves HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | | | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
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11
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Benesch MGK, Wu R, Tang X, Brindley DN, Ishikawa T, Takabe K. Autotaxin production in the human breast cancer tumor microenvironment mitigates tumor progression in early breast cancers. Am J Cancer Res 2023; 13:2790-2813. [PMID: 37559999 PMCID: PMC10408472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/14/2023] [Indexed: 08/11/2023] Open
Abstract
Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidate in physiological wound healing. ATX is overexpressed in many cancers to promote growth, metastasis, and treatment resistance. However, ATX expression is very low in breast cancer cells, and is instead secreted by the tumor microenvironment (TME). Paracrine ATX expression, and its effects on tumor progression, has not been robustly studied in human breast tumors. In this study, ATX expression was analyzed in over 5000 non-metastatic breast cancers from databases TCGA, METABRIC and GSE96058, dichotomized by the median. Gene set enrichment analysis (GSEA) and the xCell algorithm investigated biological functions of ATX and correlation to TME cell populations. TME ATX production was verified by single cell RNA sequencing. The highest ATX expression occurred in endothelial cells and cancer-associated fibroblasts (P<0.0001). High tumor ATX expression correlated to increased adipocyte, fibroblast, and endothelial cell fractions (P<0.01), and GSEA demonstrated enriched immune system, tumor suppressor, pro-survival, stemness, and pro-inflammatory signaling in multiple gene sets. Tumor mutational burden was decreased, Ki67 scores were decreased, tumor infiltrating immune cell populations increased, and immune cytolytic activity scores increased (all P<0.01) for ATX-high tumors. Overall survival trends favored ATX-high tumors (hazard ratios 0.75-0.80). In summary, in human breast cancers, ATX is produced by the TME, and in non-metastatic tumors, high levels correlate with an anti-tumor phenotype. Because pre-clinical models use aggressive pro-metastatic cell lines where ATX-mediated signaling promotes tumorigenesis, further research is required to verify an anti-to-pro-tumor phenotype switch with breast cancer progression and/or treatment resistance.
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Affiliation(s)
- Matthew GK Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Xiaoyun Tang
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of AlbertaEdmonton, Alberta T6G 2H7, Canada
| | - David N Brindley
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of AlbertaEdmonton, Alberta T6G 2H7, Canada
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
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12
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Högberg J, Järnberg J. Approaches for the setting of occupational exposure limits (OELs) for carcinogens. Crit Rev Toxicol 2023:1-37. [PMID: 37366107 DOI: 10.1080/10408444.2023.2218887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/12/2023] [Accepted: 05/22/2023] [Indexed: 06/28/2023]
Abstract
This article addresses issues of importance for occupational exposure limits (OELs) and chemical carcinogens with a focus on non-threshold carcinogens. It comprises scientific as well as regulatory issues. It is an overview, not a comprehensive review. A central topic is mechanistic research and insights, and its implications for cancer risk assessment. Alongside scientific advancements, the approaches of hazard identification and qualitative and quantitative risk assessment have developed over the years. The key steps in a quantitative risk assessment are outlined, with special attention given to the dose-response assessment and the derivation of an OEL using risk calculations or default assessment factors. The work procedures of several bodies performing cancer hazard identifications and quantitative risk assessments, as well as regulatory procedures to derive OELs for non-threshold carcinogens, are presented. Non-threshold carcinogens for which the European Union (EU) introduced binding OELs in 2017-2019 serve as illustrations together with some currently used strategies in the EU and elsewhere. Available knowledge supports the derivation of health-based OELs (Hb-OELs) for non-threshold carcinogens, and the use of a risk-based approach with low-dose linear extrapolation (linear non-threshold, LNT) as the default for non-threshold carcinogens. However, there is a need to develop methods that allow recent years' advances in cancer research to be used for improving risk estimates. It is recommended that defined risk levels (terminology and numerical values) are harmonised, and that both collective and individual risks are considered and clearly communicated. Socioeconomic aspects should be dealt with transparently and separated from the scientific health risk assessment.
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Affiliation(s)
- Johan Högberg
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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Benesch MGK, Wu R, Tang X, Brindley DN, Ishikawa T, Takabe K. Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression. Int J Mol Sci 2023; 24:9812. [PMID: 37372960 PMCID: PMC10298074 DOI: 10.3390/ijms24129812] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.
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Affiliation(s)
- Matthew G. K. Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Rongrong Wu
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan; (R.W.); (T.I.)
| | - Xiaoyun Tang
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; (X.T.); (D.N.B.)
| | - David N. Brindley
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; (X.T.); (D.N.B.)
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan; (R.W.); (T.I.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan; (R.W.); (T.I.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
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Thangam C, Cyril R, Sekar R, Jayasree R, Ramachandran V, Langeswaran K, Asir AB, Subbaraj GK. Role of phospholipase A2 in squamous cell carcinoma and breast cancer. PHOSPHOLIPASES IN PHYSIOLOGY AND PATHOLOGY 2023:315-335. [DOI: 10.1016/b978-0-323-95697-0.00010-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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15
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Shimura T, Kurano M, Okamoto K, Jubishi D, Hashimoto H, Kano K, Igarashi K, Shimamoto S, Aoki J, Moriya K, Yatomi Y. Decrease in serum levels of autotaxin in COVID-19 patients. Ann Med 2022; 54:3189-3200. [PMID: 36369824 PMCID: PMC9665086 DOI: 10.1080/07853890.2022.2143554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION In order to identify therapeutic targets in Coronavirus disease 2019 (COVID-19), it is important to identify molecules involved in the biological responses that are modulated in COVID-19. Lysophosphatidic acids (LPAs) are involved in the pulmonary inflammation and fibrosis are one of the candidate molecules. The aim of this study was to evaluate the association between the serum levels of autotaxin (ATX), which are enzymes involved in the synthesis of lysophosphatidic acids. MATERIAL AND METHODS We enrolled 134 subjects with COVID-19 and 58 normal healthy subjects for the study. We measured serum ATX levels longitudinally in COVID-19 patients and investigated the time course and the association with severity and clinical parameters. RESULTS The serum ATX levels were reduced in all patients with COVID-19, irrespective of the disease severity, and were negatively associated with the serum CRP, D-dimer, and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels. DISCUSSION Considering the biological properties of LPAs in the pulmonary inflammation and fibrosis, modulation of ATX might be compensatory biological responses to suppress immunological overreaction especially in the lung, which is an important underlying mechanism for the mortality of the disease. CONCLUSIONS COVID-19 patients showed a decrease in the serum levels of ATX, irrespective of the disease severity. Key MessagesAutotaxin (ATX) is an enzyme involved in the synthesis of lysophosphatidic acid (LPA), which has been reported to be involved in pulmonary inflammation and fibrosis. Patients with COVID-19 show decrease in the serum levels of ATX. Modulation of ATX might be compensatory biological responses to suppress immunological overreaction.
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Affiliation(s)
- Takuya Shimura
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.,Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koh Okamoto
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Daisuke Jubishi
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Hideki Hashimoto
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Kanagawa, Japan
| | | | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Kyoji Moriya
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.,Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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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: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar 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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17
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Kalamatianos T, Drosos E, Magkrioti C, Nikitopoulou I, Koutsarnakis C, Kotanidou A, Paraskevas GP, Aidinis V, Stranjalis G. Autotaxin Activity in Chronic Subdural Hematoma: A Prospective Clinical Study. Diagnostics (Basel) 2022; 12:diagnostics12081865. [PMID: 36010216 PMCID: PMC9406550 DOI: 10.3390/diagnostics12081865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/18/2022] Open
Abstract
Autotaxin (ATX) is the ectoenzyme producing the bulk of lysophosphatidic acid (LPA) in circulation. ATX and LPA-mediated signaling (the ATX-LPA axis) play critical roles in the vascular and nervous system development. In adults, this axis contributes to diverse processes, including coagulation, inflammation, fibroproliferation and angiogenesis under physiological and/or pathophysiological conditions. Given evidence implicating several of these processes in chronic subdural hematoma (CSDH) pathogenesis and development, we assessed ATX activity in CSDH patients. Twenty-eight patients were recruited. Blood and hematoma fluid were collected. Enzymatic assays were used to establish serum and hematoma ATX activity. Enzyme-linked immunosorbent assays were used to establish hematoma beta trace (BT) levels, a cerebrospinal fluid (CSF) marker, in a hematoma. ATX activity was nearly three folds higher in hematoma compared to serum (P < 0.001). There was no significant correlation between BT levels and ATX activity in a hematoma. The present results show, for the first time, that ATX is catalytically active in the hematoma fluid of CSDH patients. Moreover, our findings of significantly elevated ATX activity in hematoma compared to serum, implicate the ATX-LPA axis in CSDH pathophysiology. The CSF origin of ATX could not be inferred with the present results. Additional research is warranted to establish the significance of the ATX-LPA axis in CSDH and its potential as a biomarker and/or therapeutic target.
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Affiliation(s)
- Theodosis Kalamatianos
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
- Hellenic Centre for Neurosurgery Research, “Professor Petros S. Kokkalis”, 106 75 Athens, Greece
- Correspondence:
| | - Evangelos Drosos
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
| | - Christiana Magkrioti
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 166 72 Athens, Greece; (C.M.); (V.A.)
| | - Ioanna Nikitopoulou
- GP Livanos and M Simou Laboratories, 1st Department of Critical Care & Pulmonary Services, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece;
| | - Christos Koutsarnakis
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
| | - Anastasia Kotanidou
- 1st Department of Critical Care & Pulmonary Services, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece;
| | - George P. Paraskevas
- 2nd Department of Neurology, School of Medicine, “Attikon” General Hospital, National and Kapodistrian University of Athens, 124 62 Athens, Greece;
| | - Vassilis Aidinis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 166 72 Athens, Greece; (C.M.); (V.A.)
| | - George Stranjalis
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
- Hellenic Centre for Neurosurgery Research, “Professor Petros S. Kokkalis”, 106 75 Athens, Greece
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18
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Hargreaves A, Barry ST, Bigley A, Kendrew J, Price S. Tumors Modulate the Systemic Vascular Response to Anti‐angiogenic Therapy. J Appl Toxicol 2022; 42:1371-1384. [PMID: 35152467 PMCID: PMC9543901 DOI: 10.1002/jat.4301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 02/04/2022] [Accepted: 02/04/2022] [Indexed: 11/13/2022]
Abstract
Toxicologic evaluation of new drug candidates routinely utilizes healthy animals. In oncology, there remains a limited understanding of the effects of novel test candidates in a diseased host. For vascular modulating agents (VMAs), an increased understanding of preclinical tumour–host interaction, and its potential to exacerbate or alleviate ‘off‐target’ effects of anti‐angiogenic administration, could aid in the prediction of adverse clinical outcomes in a defined cancer patient. We have previously reported that the implantation and growth of a range of human‐ and mouse‐derived tumours leads to structural vascular and, potentially, functional signalling changes within host mouse endocrine tissues, indicating possible roles for tumour‐ and host‐derived cytokines/growth factors and the liberation of myeloid‐derived suppressor cells in this phenomenon. Here, we further demonstrate that the growth of the Calu‐6 xenograft is associated with a resistance to VMA‐induced mouse peripheral endocrine vascular rarefaction (toxicity), with potential functional impact, notably with respect to mixed tyrosine kinase inhibition. The pathogenesis of these findings indicates a potential role for both tumour‐ and host‐derived basic fibroblast growth factor (bFGF), with associated upregulation in the intra‐tumoural autotaxin‐lysophosphatic acid signalling axis. The growth of the Calu‐6 xenograft is associated with a resistance to vascular modulating agent‐induced mouse peripheral endocrine vascular rarefaction (toxicity), with potential functional impact, notably with respect to mixed tyrosine kinase inhibition. The pathogenesis of these findings indicates a potential role for basic fibroblast growth factor, with associated upregulation in the autotaxin‐lysophosphatic acid signalling axis.
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Affiliation(s)
- Adam Hargreaves
- PathCelerate Ltd., Alderley Park, Mereside, Macclesfield England, UK
- University of Surrey, University Campus, Guildford England, UK
| | - Simon T. Barry
- Bioscience, Early Oncology, AstraZeneca, Cambridge England, UK
| | - Alison Bigley
- OracleBio Ltd., BioCity Scotland, North Lanarkshire Scotland, UK
| | - Jane Kendrew
- Sygnature Discovery Ltd., Alderley Park, Mereside, Macclesfield England, UK
| | - Shirley Price
- University of Surrey, University Campus, Guildford England, UK
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19
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Matas-Rico E, Frijlink E, van der Haar Àvila I, Menegakis A, van Zon M, Morris AJ, Koster J, Salgado-Polo F, de Kivit S, Lança T, Mazzocca A, Johnson Z, Haanen J, Schumacher TN, Perrakis A, Verbrugge I, van den Berg JH, Borst J, Moolenaar WH. Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8 + T cells. Cell Rep 2021; 37:110013. [PMID: 34788605 PMCID: PMC8761359 DOI: 10.1016/j.celrep.2021.110013] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 10/07/2021] [Accepted: 10/26/2021] [Indexed: 01/22/2023] Open
Abstract
Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1–6. ATX/LPA promotes tumor cell migration and metastasis via LPAR1 and T cell motility via LPAR2, yet its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) and circulating CD8+ T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T cell repulsion predominantly involves Gα12/13-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor regression. Moreover, single-cell data from melanoma tumors are consistent with intratumoral ATX acting as a T cell repellent. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities. Through LPA production, ATX modulates the tumor microenvironment in autocrine-paracrine manners. Matas-Rico et al. show that ATX/LPA is chemorepulsive for T cells with a dominant inhibitory role for Gα12/13-coupled LPAR6. Upon anticancer vaccination, tumor-intrinsic ATX suppresses the infiltration of CD8+ T cells without affecting their cytotoxic quality.
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Affiliation(s)
- Elisa Matas-Rico
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Elselien Frijlink
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Irene van der Haar Àvila
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Apostolos Menegakis
- Oncode Institute, Utrecht, the Netherlands; Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Maaike van Zon
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Andrew J Morris
- Division of Cardiovascular Medicine, Gill Heart Institute and Lexington Veterans Affairs Medical Center, University of Kentucky, Lexington, KY, USA
| | - Jan Koster
- Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, Amsterdam, the Netherlands
| | - Fernando Salgado-Polo
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Sander de Kivit
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Telma Lança
- Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Zoë Johnson
- iOnctura SA, Campus Biotech Innovation Park, Geneva, Switzerland
| | - John Haanen
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Ton N Schumacher
- Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Anastassis Perrakis
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Inge Verbrugge
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Joost H van den Berg
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jannie Borst
- Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
| | - Wouter H Moolenaar
- Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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20
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Zsila F, Ricci M, Szigyártó IC, Singh P, Beke-Somfai T. Quorum Sensing Pseudomonas Quinolone Signal Forms Chiral Supramolecular Assemblies With the Host Defense Peptide LL-37. Front Mol Biosci 2021; 8:742023. [PMID: 34708076 PMCID: PMC8542694 DOI: 10.3389/fmolb.2021.742023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/03/2021] [Indexed: 12/21/2022] Open
Abstract
Host defense antimicrobial peptides (HDPs) constitute an integral component of the innate immune system having nonspecific activity against a broad spectrum of microorganisms. They also have diverse biological functions in wound healing, angiogenesis, and immunomodulation, where it has also been demonstrated that they have a high affinity to interact with human lipid signaling molecules. Within bacterial biofilms, quorum sensing (QS), the vital bacterial cell-to-cell communication system, is maintained by similar diffusible small molecules which control phenotypic traits, virulence factors, biofilm formation, and dispersion. Efficient eradication of bacterial biofilms is of particular importance as these colonies greatly help individual cells to tolerate antibiotics and develop antimicrobial resistance. Regarding the antibacterial function, for several HDPs, including the human cathelicidin LL-37, affinity to eradicate biofilms can exceed their activity to kill individual bacteria. However, related underlying molecular mechanisms have not been explored yet. Here, we employed circular dichroism (CD) and UV/VIS spectroscopic analysis, which revealed that LL-37 exhibits QS signal affinity. This archetypal representative of HDPs interacts with the Pseudomonas quinolone signal (PQS) molecules, producing co-assemblies with peculiar optical activity. The binding of PQS onto the asymmetric peptide chains results in chiral supramolecular architectures consisting of helically disposed, J-aggregated molecules. Besides the well-known bacterial membrane disruption activity, our data propose a novel action mechanism of LL-37. As a specific case of the so-called quorum quenching, QS signal molecules captured by the peptide are sequestered inside co-assemblies, which may interfere with the microbial QS network helping to prevent and eradicate bacterial infections.
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Affiliation(s)
- Ferenc Zsila
- Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences (MTA), Budapest, Hungary
| | | | | | | | - Tamás Beke-Somfai
- Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences (MTA), Budapest, Hungary
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Jin Y, Kim EN, Lim JH, Kim HD, Ban TH, Yang CW, Park CW, Choi BS. Role of Aberrantly Activated Lysophosphatidic Acid Receptor 1 Signaling Mediated Inflammation in Renal Aging. Cells 2021; 10:cells10102580. [PMID: 34685560 PMCID: PMC8534041 DOI: 10.3390/cells10102580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/25/2021] [Accepted: 09/26/2021] [Indexed: 11/16/2022] Open
Abstract
The increasing load of senescent cells is a source of aging, and chronic inflammation plays a pivotal role in cellular senescence. In addition, senescent renal tubular epithelial cells are closely associated with renal aging. Lysophosphatidic acid (LPA) is a bioactive lipid mainly produced by the catalytic action of autotaxin (ATX), and its ligation to LPA receptor-1 (LPAR1) is associated with chronic inflammation and renal fibrosis; however, its role in renal aging is unclear. Male 2-, 12-, and 24-month-old C57BL/6 mice and Human renal proximal tubular epithelial cells (HRPTEpiC) were used in the present study. DNA damage and oxidative stress-induced senescence were simulated using doxorubicin (DOXO) and H2O2, respectively. The aged kidney showed decreased renal function, increased fractional mesangial area, and tubulointerstitial fibrosis. Both aged kidney and senescent cells showed increased levels of LPAR1, Nuclear factor κB (NF-κB), and inflammatory cytokines. In addition, LPAR1-knockdown reduced NF-κB and subsequent inflammatory cytokine induction, and NF-κB-knockdown resulted in decreased LPAR1 expression. Our study revealed a positive feedback loop between LPAR1 and NF-κB, which reinforces the role of inflammatory response, suggesting that blocking of aberrantly activated LPAR1 may reduce excessive inflammation, thereby providing a new possible therapeutic strategy to attenuate renal aging.
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Affiliation(s)
- Yongjie Jin
- College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
| | - Eun Nim Kim
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Korea
| | - Ji Hee Lim
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Korea
- The Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Hyung Duk Kim
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Korea
| | - Tae Hyun Ban
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Eunpyeong, St. Mary’s Hospital, Seoul 03312, Korea
| | - Chul Woo Yang
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Korea
| | - Cheol Whee Park
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Korea
- The Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Bum Soon Choi
- Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea; (E.N.K.); (J.H.L.); (H.D.K.); (T.H.B.); (C.W.Y.); (C.W.P.)
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Eunpyeong, St. Mary’s Hospital, Seoul 03312, Korea
- Correspondence:
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22
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Zhao F, An R, Wang L, Shan J, Wang X. Specific Gut Microbiome and Serum Metabolome Changes in Lung Cancer Patients. Front Cell Infect Microbiol 2021; 11:725284. [PMID: 34527604 PMCID: PMC8435782 DOI: 10.3389/fcimb.2021.725284] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/10/2021] [Indexed: 12/26/2022] Open
Abstract
Background Lung cancer (LC) is one of the most aggressive, prevalent and fatal malignancies. Gut microbes and their associated metabolites are thought to cause and modulate LC development, albeit influenced by the host genetic make-up and environment. Herein, we identified and classified gut microbiota and serum metabolites associated with LC. Methods Stool samples were collected from 41 LC patients and 40 healthy volunteers. The gut microbiota was analyzed using 16S rRNA gene sequencing. Serum samples were collected from the same LC patients (n=30) and healthy volunteers (n=30) and serum metabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). Microbiome and metabolome data were analyzed separately and integrated for combined analysis using various bioinformatics methods. Results Serum metabolomics uncovered 870 metabolites regulated in 76 metabolic pathways in both groups. Microbial diversity analyses identified 15967 operational taxonomic units (OTUs) in groups. Of these, the abundance of 232 OTUs was significantly different between HC and LC groups. Also, serum levels of glycerophospholipids (LysoPE 18:3, LysoPC 14:0, LysoPC 18:3), Imidazopyrimidines (Hypoxanthine), AcylGlcADG 66:18; AcylGlcADG (22:6/22:6/22:6) and Acylcarnitine 11:0 were substantially different between HC and LC groups. Combined analysis correlated LC-associated microbes with metabolites, such as Erysipelotrichaceae_UCG_003, Clostridium and Synergistes with glycerophospholipids. Conclusions There is an intricate relationship between gut microbiome and levels of several metabolites such as glycerophospholipids and imidazopyrimidines. Microbial-associated metabolites are potential diagnostic biomarkers and therapeutic targets for LC.
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Affiliation(s)
- Feng Zhao
- Department of Laboratory Medicine, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Rui An
- Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Laboratory Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liqian Wang
- Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jikang Shan
- Department of Laboratory Medicine, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianjun Wang
- Department of Laboratory Medicine, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
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23
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Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease. Int J Mol Sci 2021; 22:ijms22179575. [PMID: 34502491 PMCID: PMC8431043 DOI: 10.3390/ijms22179575] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 01/12/2023] Open
Abstract
Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy.
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24
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Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials. Cells 2021; 10:cells10071629. [PMID: 34209775 PMCID: PMC8306951 DOI: 10.3390/cells10071629] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.
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25
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Birgbauer E. Lysophosphatidic Acid Signalling in Nervous System Development and Function. Neuromolecular Med 2021; 23:68-85. [PMID: 33151452 PMCID: PMC11420905 DOI: 10.1007/s12017-020-08630-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023]
Abstract
One class of molecules that are now coming to be recognized as essential for our understanding of the nervous system are the lysophospholipids. One of the major signaling lysophospholipids is lysophosphatidic acid, also known as LPA. LPA activates a variety of G protein-coupled receptors (GPCRs) leading to a multitude of physiological responses. In this review, I describe our current understanding of the role of LPA and LPA receptor signaling in the development and function of the nervous system, especially the central nervous system (CNS). In addition, I highlight how aberrant LPA receptor signaling may underlie neuropathological conditions, with important clinical application.
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Affiliation(s)
- Eric Birgbauer
- Department of Biology, Winthrop University, Rock Hill, SC, USA.
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26
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Jinno N, Yoshida M, Hayashi K, Naitoh I, Hori Y, Natsume M, Kato A, Kachi K, Asano G, Atsuta N, Sahashi H, Kataoka H. Autotaxin in ascites promotes peritoneal dissemination in pancreatic cancer. Cancer Sci 2021; 112:668-678. [PMID: 33053268 PMCID: PMC7893983 DOI: 10.1111/cas.14689] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/30/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022] Open
Abstract
Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates the progression of various cancers. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX-LPA axis in malignant ascites in PDAC and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC-1 and PANC-1, showed that ATX-LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF-8380. An in vivo study showed that PF-8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC.
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Affiliation(s)
- Naruomi Jinno
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Michihiro Yoshida
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Kazuki Hayashi
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Itaru Naitoh
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Yasuki Hori
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Makoto Natsume
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Akihisa Kato
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Kenta Kachi
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Go Asano
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Naoki Atsuta
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Hidenori Sahashi
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Hiromi Kataoka
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
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Annett S, Moore G, Robson T. Obesity and Cancer Metastasis: Molecular and Translational Perspectives. Cancers (Basel) 2020; 12:E3798. [PMID: 33339340 PMCID: PMC7766668 DOI: 10.3390/cancers12123798] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is a modern health problem that has reached pandemic proportions. It is an established risk factor for carcinogenesis, however, evidence for the contribution of adipose tissue to the metastatic behavior of tumors is also mounting. Over 90% of cancer mortality is attributed to metastasis and metastatic tumor cells must communicate with their microenvironment for survival. Many of the characteristics observed in obese adipose tissue strongly mirror the tumor microenvironment. Thus in the case of prostate, pancreatic and breast cancer and esophageal adenocarcinoma, which are all located in close anatomical proximity to an adipose tissue depot, the adjacent fat provides an ideal microenvironment to enhance tumor growth, progression and metastasis. Adipocytes provide adipokines, fatty acids and other soluble factors to tumor cells whilst immune cells infiltrate the tumor microenvironment. In addition, there are emerging studies on the role of the extracellular vesicles secreted from adipose tissue, and the extracellular matrix itself, as drivers of obesity-induced metastasis. In the present review, we discuss the major mechanisms responsible for the obesity-metastatic link. Furthermore, understanding these complex mechanisms will provide novel therapies to halt the tumor-adipose tissue crosstalk with the ultimate aim of inhibiting tumor progression and metastatic growth.
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Affiliation(s)
| | | | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Science, 123 St Stephen’s Green, Dublin D02 YN77, Ireland; (S.A.); (G.M.)
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Kim H, Kim M, Myoung K, Kim W, Ko J, Kim KP, Cho EG. Comparative Lipidomic Analysis of Extracellular Vesicles Derived from Lactobacillus plantarum APsulloc 331261 Living in Green Tea Leaves Using Liquid Chromatography-Mass Spectrometry. Int J Mol Sci 2020; 21:E8076. [PMID: 33138039 PMCID: PMC7663264 DOI: 10.3390/ijms21218076] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/26/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023] Open
Abstract
Lactobacillus plantarum is a popular probiotic species due to its safe and beneficial effects on humans; therefore, novel L. plantarum strains have been isolated and identified from various dietary products. Given that bacteria-derived extracellular vesicles (EVs) have been considered as efficient carriers of bioactive materials and shown to evoke cellular responses effectively, L. plantarum-derived EVs are expected to efficiently elicit health benefits. Herein, we identified L. plantarum APsulloc 331261 living in green tea leaves and isolated EVs from the culture medium. We performed quantitative lipidomic analysis of L. plantarum APsulloc 331261 derived EVs (LEVs) using liquid chromatography-mass spectrometry. In comparison to L. plantarum APsulloc 331261, in LEVs, 67 of 320 identified lipid species were significantly increased and 19 species were decreased. In particular, lysophosphatidylserine(18:4) and phosphatidylcholine(32:2) were critically increased, showing over 21-fold enrichment in LEVs. In addition, there was a notable difference between LEVs and the parent cells in the composition of phospholipids. Our results suggest that the lipidomic profile of bacteria-derived EVs is different from that of the parent cells in phospholipid content and composition. Given that lipids are important components of EVs, quantitative and comparative analyses of EV lipids may improve our understanding of vesicle biogenesis and lipid-mediated intercellular communication within or between living organisms.
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Affiliation(s)
- Hyoseon Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Korea; (H.K.); (M.K.)
| | - Minjung Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Korea; (H.K.); (M.K.)
| | - Kilsun Myoung
- Basic Research and Innovation Division, R&D Center, Amorepacific Corporation, Yongin 17074, Korea; (K.M.); (W.K.); (J.K.)
| | - Wanil Kim
- Basic Research and Innovation Division, R&D Center, Amorepacific Corporation, Yongin 17074, Korea; (K.M.); (W.K.); (J.K.)
- Division of Cosmetic Science & Technology, Daegu Haany University, Gyeongsan 38610, Korea
| | - Jaeyoung Ko
- Basic Research and Innovation Division, R&D Center, Amorepacific Corporation, Yongin 17074, Korea; (K.M.); (W.K.); (J.K.)
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Korea; (H.K.); (M.K.)
- Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul 02453, Korea
| | - Eun-Gyung Cho
- Basic Research and Innovation Division, R&D Center, Amorepacific Corporation, Yongin 17074, Korea; (K.M.); (W.K.); (J.K.)
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Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction. J Mol Cell Cardiol 2020; 149:95-114. [PMID: 33017574 DOI: 10.1016/j.yjmcc.2020.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 09/25/2020] [Accepted: 09/26/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood. APPROACH AND RESULTS We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3Δ mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson's Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis. CONCLUSION ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury.
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Banerjee S, Norman DD, Deng S, Fakayode SO, Lee SC, Parrill AL, Li W, Miller DD, Tigyi GJ. Molecular modelling guided design, synthesis and QSAR analysis of new small molecule non-lipid autotaxin inhibitors. Bioorg Chem 2020; 103:104188. [PMID: 32890995 PMCID: PMC8163515 DOI: 10.1016/j.bioorg.2020.104188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/18/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023]
Abstract
The lysophospholipase D autotaxin (ATX) generates lysophosphatidic acid (LPA) that activates six cognate G-protein coupled receptors (GPCR) in cancerous cells, promoting their motility and invasion. Four novel compounds were generated aided by molecular docking guided design and synthesis techniques to obtain new dual inhibitors of ATX and the lysophosphatidic acid receptor subtype 1 (LPAR1). Biological evaluation of these compounds revealed two compounds, 10 and 11, as new ATX enzyme inhibitors with potencies in the range of 218-220 nM and water solubility (>100 µg/mL), but with no LPAR1 inhibitory activity. A QSAR model was generated that included four newly designed compounds and twenty-one additional compounds that we have reported previously. The QSAR model provided excellent predictability of the pharmacological activity and potency among structurally related drug candidates. This model will be highly useful in guiding the synthesis of new ATX inhibitors in the future.
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Affiliation(s)
- Souvik Banerjee
- Department of Physical Sciences, University of Arkansas Fort Smith, Fort Smith, AR 72913, USA; Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Shanshan Deng
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Sayo O Fakayode
- Department of Physical Sciences, University of Arkansas Fort Smith, Fort Smith, AR 72913, USA
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Abby L Parrill
- Department of Chemistry, Computational Research on Material Institute, The University of Memphis, Memphis, TN 38152, USA
| | - Wei Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Duane D Miller
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Gabor J Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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31
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Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer. Int J Mol Sci 2020; 21:ijms21165938. [PMID: 32824846 PMCID: PMC7460696 DOI: 10.3390/ijms21165938] [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] [Scholar Register] [Received: 07/02/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidate (LPA), which signals through six G-protein coupled receptors, promoting tumor growth, metastasis, and survival from chemotherapy and radiotherapy. Many cancer cells produce ATX, but breast cancer cells express little ATX. In breast tumors, ATX is produced by tumor-associated stroma. Breast tumors are also surrounded by adipose tissue, which is a major bodily source of ATX. In mice, a high-fat diet increases adipocyte ATX production. ATX production in obesity is also increased because of low-level inflammation in the expanded adipose tissue. This increased ATX secretion and consequent LPA signaling is associated with decreased adiponectin production, which results in adverse metabolic profiles and glucose homeostasis. Increased ATX production by inflamed adipose tissue may explain the obesity-breast cancer association. Breast tumors produce inflammatory mediators that stimulate ATX transcription in tumor-adjacent adipose tissue. This drives a feedforward inflammatory cycle since increased LPA signaling increases production of more inflammatory mediators and cyclooxygenase-2. Inhibiting ATX activity, which has implications in breast cancer adjuvant treatments, attenuates this cycle. Targeting ATX activity and LPA signaling may potentially increase chemotherapy and radiotherapy efficacy, and decrease radiation-induced fibrosis morbidity independently of breast cancer type because most ATX is not derived from breast cancer cells.
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Zulfikar S, Mulholland S, Adamali H, Barratt SL. Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives. Clin Pharmacol 2020; 12:97-108. [PMID: 32765123 PMCID: PMC7367740 DOI: 10.2147/cpaa.s228362] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/17/2020] [Indexed: 12/18/2022] Open
Abstract
Idiopathic pulmonary fibrosis is a progressive fibrosing interstitial lung disease for which there is no known cure. Currently available therapeutic options have been shown at best to slow the progression of the disease and thus there remains an urgent unmet need to identify new therapies. In this article, we will discuss the mechanisms of action, pre-clinical and clinical trial data surrounding inhibitors of the autotaxin-lysophosphatidic acid axis, which show promise as emerging novel therapies for fibrotic lung disease.
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Affiliation(s)
- Sabrina Zulfikar
- Bristol Interstitial Lung Disease Service, North Bristol NHS Trust, Bristol, UK
| | - Sarah Mulholland
- Bristol Interstitial Lung Disease Service, North Bristol NHS Trust, Bristol, UK
| | - Huzaifa Adamali
- Bristol Interstitial Lung Disease Service, North Bristol NHS Trust, Bristol, UK
| | - Shaney L Barratt
- Bristol Interstitial Lung Disease Service, North Bristol NHS Trust, Bristol, UK
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Cuozzo JW, Clark MA, Keefe AD, Kohlmann A, Mulvihill M, Ni H, Renzetti LM, Resnicow DI, Ruebsam F, Sigel EA, Thomson HA, Wang C, Xie Z, Zhang Y. Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry. J Med Chem 2020; 63:7840-7856. [PMID: 32584034 DOI: 10.1021/acs.jmedchem.0c00688] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.
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Affiliation(s)
- John W Cuozzo
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Matthew A Clark
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Anthony D Keefe
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Anna Kohlmann
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Mark Mulvihill
- X-Rx, Inc., 430 East 29th Street, Suite 1060, New York, New York 10016, United States
| | - Haihong Ni
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Louis M Renzetti
- X-Rx, Inc., 430 East 29th Street, Suite 1060, New York, New York 10016, United States
| | - Daniel I Resnicow
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Frank Ruebsam
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Eric A Sigel
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Heather A Thomson
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
| | - Ce Wang
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Zhifeng Xie
- BioDuro, LLC, Building E, No. 29 Life Science Park Road, Changping District, Beijing 102206, China
| | - Ying Zhang
- X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States
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Signalling by lysophosphatidate and its health implications. Essays Biochem 2020; 64:547-563. [DOI: 10.1042/ebc20190088] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023]
Abstract
AbstractExtracellular lysophosphatidate (LPA) signalling is regulated by the balance of LPA formation by autotaxin (ATX) versus LPA degradation by lipid phosphate phosphatases (LPP) and by the relative expressions of six G-protein-coupled LPA receptors. These receptors increase cell proliferation, migration, survival and angiogenesis. Acute inflammation produced by tissue damage stimulates ATX production and LPA signalling as a component of wound healing. If inflammation does not resolve, LPA signalling becomes maladaptive in conditions including arthritis, neurologic pain, obesity and cancers. Furthermore, LPA signalling through LPA1 receptors promotes fibrosis in skin, liver, kidneys and lungs. LPA also promotes the spread of tumours to other organs (metastasis) and the pro-survival properties of LPA explain why LPA counteracts the effects of chemotherapeutic agents and radiotherapy. ATX is secreted in response to radiation-induced DNA damage during cancer treatments and this together with increased LPA1 receptor expression leads to radiation-induced fibrosis. The anti-inflammatory agent, dexamethasone, decreases levels of inflammatory cytokines/chemokines. This is linked to a coordinated decrease in the production of ATX and LPA1/2 receptors and increased LPA degradation through LPP1. These effects explain why dexamethasone attenuates radiation-induced fibrosis. Increased LPA signalling is also associated with cardiovascular disease including atherosclerosis and deranged LPA signalling is associated with pregnancy complications including preeclampsia and intrahepatic cholestasis of pregnancy. LPA contributes to chronic inflammation because it stimulates the secretion of inflammatory cytokines/chemokines, which increase further ATX production and LPA signalling. Attenuating maladaptive LPA signalling provides a novel means of treating inflammatory diseases that underlie so many important medical conditions.
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Feng Y, Mischler WJ, Gurung AC, Kavanagh TR, Androsov G, Sadow PM, Herbert ZT, Priolo C. Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis. Cancer Res 2020; 80:2751-2763. [PMID: 32393662 DOI: 10.1158/0008-5472.can-19-2884] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 03/25/2020] [Accepted: 05/05/2020] [Indexed: 12/14/2022]
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM. SIGNIFICANCE: This study identifies activation of the ATX-LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.
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Affiliation(s)
- You Feng
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - William J Mischler
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Ashish C Gurung
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Taylor R Kavanagh
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Grigoriy Androsov
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Peter M Sadow
- Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Zachary T Herbert
- Harvard Medical School, Boston, Massachusetts
- Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Carmen Priolo
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts
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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] [Scholar 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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Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis. Cancers (Basel) 2020; 12:cancers12040999. [PMID: 32325715 PMCID: PMC7226295 DOI: 10.3390/cancers12040999] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 02/06/2023] Open
Abstract
We recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA1/2 receptors. We also established that dexamethasone decreases autotaxin production and LPA signaling in non-irradiated adipose tissue. In the present study, we showed that dexamethasone attenuated the radiation-induced increases in autotaxin activity and the concentrations of inflammatory mediators in cultured human adipose tissue. We also exposed a breast fat pad in mice to three daily 7.5 Gy fractions of X-rays. Dexamethasone attenuated radiation-induced increases in autotaxin activity in plasma and mammary adipose tissue and LPA1 receptor levels in adipose tissue after 48 h. DEX treatment during five daily fractions of 7.5 Gy attenuated fibrosis by ~70% in the mammary fat pad and underlying lungs at 7 weeks after radiotherapy. This was accompanied by decreases in CXCL2, active TGF-β1, CTGF and Nrf2 at 7 weeks in adipose tissue of dexamethasone-treated mice. Autotaxin was located at the sites of fibrosis in breast tissue and in the underlying lungs. Consequently, our work supports the premise that increased autotaxin production and lysophosphatidate signaling contribute to radiotherapy-induced breast fibrosis and that dexamethasone attenuated the development of fibrosis in part by blocking this process.
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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] [Scholar 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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Benesch MGK, Tang X, Brindley DN. Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae. Cancers (Basel) 2020; 12:cancers12020374. [PMID: 32041123 PMCID: PMC7072337 DOI: 10.3390/cancers12020374] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/27/2020] [Accepted: 02/01/2020] [Indexed: 02/06/2023] Open
Abstract
After a decade of intense preclinical investigations, the first in-class autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers.
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Affiliation(s)
- Matthew G. K. Benesch
- Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL AlB 3V6, Canada
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
| | - Xiaoyun Tang
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
| | - David N. Brindley
- Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
- Correspondence: ; Tel.: +1-780-492-2078
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40
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The roles of autotaxin/lysophosphatidic acid in immune regulation and asthma. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158641. [PMID: 32004685 DOI: 10.1016/j.bbalip.2020.158641] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/26/2019] [Accepted: 01/23/2020] [Indexed: 12/18/2022]
Abstract
Lysophosphatidic acid (LPA) species are present in almost all organ systems and play diverse roles through its receptors. Asthma is an airway disease characterized by chronic allergic inflammation where various innate and adaptive immune cells participate in establishing Th2 immune response. Here, we will review the contribution of LPA and its receptors to the functions of immune cells that play a key role in establishing allergic airway inflammation and aggravation of allergic asthma.
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41
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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: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar 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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Zhong S, Jeong JH, Chen Z, Chen Z, Luo JL. Targeting Tumor Microenvironment by Small-Molecule Inhibitors. Transl Oncol 2019; 13:57-69. [PMID: 31785429 PMCID: PMC6909103 DOI: 10.1016/j.tranon.2019.10.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment (TME) is a hypoxic, acidic, and immune/inflammatory cell–enriched milieu that plays crucial roles in tumor development, growth, progression, and therapy resistance. Targeting TME is an attractive strategy for the treatment of solid tumors. Conventional cancer chemotherapies are mostly designed to directly kill cancer cells, and the effectiveness is always compromised by their penetration and accessibility to cancer cells. Small-molecule inhibitors, which exhibit good penetration and accessibility, are widely studied, and many of them have been successfully applied in clinics for cancer treatment. As TME is more penetrable and accessible than tumor cells, a lot of efforts have recently been made to generate small-molecule inhibitors that specifically target TME or the components of TME or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. In this review, we briefly summarize the recent advances of small-molecule inhibitors that target TME for the tumor treatment.
Tumor microenvironment (TME) is an indispensable part of tumor and is an important therapeutic target. TME is more penetrable and accessible than tumor cell area. Small-molecule inhibitors that target TME are very promising. The target efficiency can be improved by specific deliver and release systems.
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Affiliation(s)
- Shangwei Zhong
- The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Hunan, 410008, China; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Ji-Hak Jeong
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Zhikang Chen
- The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Hunan, 410008, China.
| | - Zihua Chen
- The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Hunan, 410008, China.
| | - Jun-Li Luo
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA.
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Repeated Fractions of X-Radiation to the Breast Fat Pads of Mice Augment Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle. Cancers (Basel) 2019; 11:cancers11111816. [PMID: 31752313 PMCID: PMC6895803 DOI: 10.3390/cancers11111816] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/07/2019] [Accepted: 11/13/2019] [Indexed: 12/31/2022] Open
Abstract
Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin–lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal “image-guided” RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNFα in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin–lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT.
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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: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar 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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Xu Y. Targeting Lysophosphatidic Acid in Cancer: The Issues in Moving from Bench to Bedside. Cancers (Basel) 2019; 11:E1523. [PMID: 31658655 PMCID: PMC6826372 DOI: 10.3390/cancers11101523] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/02/2019] [Accepted: 10/08/2019] [Indexed: 12/16/2022] Open
Abstract
Since the clear demonstration of lysophosphatidic acid (LPA)'s pathological roles in cancer in the mid-1990s, more than 1000 papers relating LPA to various types of cancer were published. Through these studies, LPA was established as a target for cancer. Although LPA-related inhibitors entered clinical trials for fibrosis, the concept of targeting LPA is yet to be moved to clinical cancer treatment. The major challenges that we are facing in moving LPA application from bench to bedside include the intrinsic and complicated metabolic, functional, and signaling properties of LPA, as well as technical issues, which are discussed in this review. Potential strategies and perspectives to improve the translational progress are suggested. Despite these challenges, we are optimistic that LPA blockage, particularly in combination with other agents, is on the horizon to be incorporated into clinical applications.
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Affiliation(s)
- Yan Xu
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut Street R2-E380, Indianapolis, IN 46202, USA.
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Hypoxia Downregulates LPP3 and Promotes the Spatial Segregation of ATX and LPP1 During Cancer Cell Invasion. Cancers (Basel) 2019; 11:cancers11091403. [PMID: 31546971 PMCID: PMC6769543 DOI: 10.3390/cancers11091403] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/07/2019] [Accepted: 09/12/2019] [Indexed: 12/16/2022] Open
Abstract
Hypoxia is a common characteristic of advanced solid tumors and a potent driver of tumor invasion and metastasis. Recent evidence suggests the involvement of autotaxin (ATX) and lysophosphatidic acid receptors (LPARs) in cancer cell invasion promoted by the hypoxic tumor microenvironment; however, the transcriptional and/or spatiotemporal control of this process remain unexplored. Herein, we investigated whether hypoxia promotes cell invasion by affecting the main enzymes involved in its production (ATX) and degradation (lipid phosphate phosphatases, LPP1 and LPP3). We report that hypoxia not only modulates the expression levels of lysophosphatidic acid (LPA) regulatory enzymes but also induces their significant spatial segregation in a variety of cancers. While LPP3 expression was downregulated by hypoxia, ATX and LPP1 were asymmetrically redistributed to the leading edge and to the trailing edge, respectively. This was associated with the opposing roles of ATX and LPPs in cell invasion. The regulated expression and compartmentalization of these enzymes of opposing function can provide an effective way to control the generation of an LPA gradient that drives cellular invasion and migration in the hypoxic zones of tumors.
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Diverse Effects of Lysophosphatidic Acid Receptors on Ovarian Cancer Signaling Pathways. JOURNAL OF ONCOLOGY 2019; 2019:7547469. [PMID: 31636669 PMCID: PMC6766155 DOI: 10.1155/2019/7547469] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/09/2019] [Accepted: 08/21/2019] [Indexed: 12/13/2022]
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid with mitogenic and growth factor-like activities affecting cell invasion, cancer progression, and resistance. It is produced mainly by autotaxin and acts on six G-protein-coupled receptors, LPAR1-6. LPA has recently been implicated as a growth factor present in ascites of ovarian cancer patients. However, mitogenic pathways stimulated by LPA via its receptors may involve any novel, thus far uncharacterized, signaling pathway(s). Here we show that three LPA receptors are involved in tumor progression by activation of both the AKT and ERK signaling pathways. CRISPR-edited LPAR2 and LPAR3 knockouts have opposing effects on ERK activation, whereas LPAR6 is involved in the activation of AKT, affecting cell migration and invasion. Our study identifies specific molecular machinery triggered by LPA and its receptors that modulates tumor cells and can serve as therapeutic target in this malignancy.
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Kraemer MP, Mao G, Hammill C, Yan B, Li Y, Onono F, Smyth SS, Morris AJ. Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid. J Lipid Res 2019; 60:1818-1828. [PMID: 31484695 DOI: 10.1194/jlr.m093096] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 08/19/2019] [Indexed: 12/12/2022] Open
Abstract
Lysophosphatidic acids (LPAs) are bioactive radyl hydrocarbon-substituted derivatives of glycerol 3-phosphate. LPA metabolism and signaling are implicated in heritable risk of coronary artery disease. Genetic and pharmacological inhibition of these processes attenuate experimental atherosclerosis. LPA accumulates in atheromas, which may be a consequence of association with LDLs. The source, regulation, and biological activity of LDL-associated LPA are unknown. We examined the effects of experimental hyperlipidemia on the levels and distribution of circulating LPA in mice. The majority of plasma LPA was associated with albumin in plasma from wild-type mice fed normal chow. LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6). Adipose-specific deficiency of the ENPP2 gene encoding the LPA-generating secreted lysophospholipase D, autotaxin (ATX), attenuated these Western diet-dependent increases in LPA. ATX-dependent increases in LDL-associated LPA were observed in isolated incubated plasma. ATX acted directly on LDL-associated lysophospholipid substrates in vitro. LDL from all human subjects examined contained LPA and was decreased by lipid-lowering drug therapies. Human and mouse plasma therefore contains a diet-sensitive LDL-associated LPA pool that might contribute to the cardiovascular disease-promoting effects of LPA.
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Affiliation(s)
- Maria P Kraemer
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY.,Lexington Veterans Affairs Medical Center, Lexington, KY
| | - Guogen Mao
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY.,Lexington Veterans Affairs Medical Center, Lexington, KY
| | - Courtney Hammill
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY.,Lexington Veterans Affairs Medical Center, Lexington, KY
| | - Baoxiang Yan
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY
| | - Yu Li
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY
| | - Fredrick Onono
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY
| | - Susan S Smyth
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY.,Lexington Veterans Affairs Medical Center, Lexington, KY
| | - Andrew J Morris
- Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY .,Lexington Veterans Affairs Medical Center, Lexington, KY
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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: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar 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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Tang X, McMullen TP, Brindley DN. Increasing the low lipid phosphate phosphatase 1 activity in breast cancer cells decreases transcription by AP-1 and expressions of matrix metalloproteinases and cyclin D1/D3. Am J Cancer Res 2019; 9:6129-6142. [PMID: 31534541 PMCID: PMC6735510 DOI: 10.7150/thno.37094] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 07/24/2019] [Indexed: 02/07/2023] Open
Abstract
Metastasis is the leading cause of mortality in breast cancer patients and lysophosphatidate (LPA) signaling promotes this process. LPA signaling is attenuated by lipid phosphate phosphatase-1 (LPP1) whose activity is decreased in cancers. Consequently, increasing LPP1 levels suppresses breast tumor growth and metastasis. This study shows that increasing LPP1 in breast cancer cells decreases transcription through cFos and cJun. This decreases production of cyclin D1/D3 and matrix metalloproteinases (MMPs), which provides new insights into the role of LPP1 in controlling tumor growth and metastasis. Methods: Invasiveness was determined by a Matrigel invasion assay. MMP expression was measured by qPCR, multiplex LASER bead technology and gelatin zymography. Levels of cJUN, cFOS, FRA1, cyclin D1, and cyclin D3 were determined by qPCR and western blotting. Collagen was determined by Picro-Sirius Red staining. Results: Increasing LPP1 expression inhibited invasion of MDA-MB-231 breast cancer cells through Matrigel. This was accompanied by decreases in expression of MMP-1, -3, -7, -9, -10, -12 and -13, which are transcriptionally regulated by the AP-1 complex. Increasing LPP1 attenuated the induction of mRNA of MMP-1, -3, cFOS, and cJUN by EGF or TNFα, but increased FRA1. LPP1 expression also decreased the induction of protein levels for cFOS and cJUN in nuclei and cytoplasmic fractions by EGF and TNFα. Protein levels of cyclin D1 and D3 were also decreased by LPP1. Although FRA1 in total cell lysates or cytoplasm was increased by LPP1, nuclear FRA1 was not affected. LPP1-induced decreases in MMPs in mouse tumors created with MDA-MB-231 cells were accompanied by increased collagen in the tumors and fewer lung metastases. Knockdown of LPP1 in MDA-MB-231 cells increased the protein levels of MMP-1 and -3. Human breast tumors also have lower levels of LPP1 and higher levels of cJUN, cFOS, MMP-1, -7, -8, -9, -12, -13, cyclin D1, and cyclin D3 relative to normal breast tissue. Conclusion: This study demonstrated that the low LPP1 expression in breast cancer cells is associated with high levels of cyclin D1/D3 and MMPs as a result of increased transcription by cFOS and cJUN. Increasing LPP1 expression provides a novel approach for decreasing transcription through AP-1, which could provide a strategy for decreasing tumor growth and metastasis.
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