|
1
|
Sak K. The path of GPR87: from a P2Y-like receptor to its role in cancer progression. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4803-4815. [PMID: 39641798 DOI: 10.1007/s00210-024-03684-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
GPR87 is a G protein-coupled seven-transmembrane receptor first described as an orphan receptor in 2001. Despite its high structural homology to several extracellular nucleotide-activated P2Y receptors and sharing conserved sequence motifs in transmembrane regions, identification of endogenous ligands from the class of nucleotides and their analogues has failed for GPR87. Although lysophosphatidic acid was proposed to be a natural ligand for this cell surface receptor, these data are preliminary and inconsistent, and IUPHAR is currently considering GPR87 as an orphan receptor. Thus, the endogenous ligands and physiological functions of GPR87 are still required to be determined and/or confirmed. The remarkably higher expression of GPR87 in human malignant tissues compared to the normal healthy ones clearly suggests that this receptor may be involved in the development and progression of cancerous neoplasms. Therefore, in this review article, the main focus is placed on the oncogenic role of GPR87 in various human malignancies, presenting it as a potential novel target site for therapeutic interventions using both humanized monoclonal antibodies and gene therapy but also selective antagonists which are still waiting for their identification. Furthermore, the importance of the expression of GPR87 as a predictive biomarker for evaluating the prognosis and overall survival of cancer patients is also highlighted.
Collapse
|
|
2
|
Biswal N, Harish R, Roshan M, Samudrala S, Jiao X, Pestell RG, Ashton AW. Role of GPCR Signaling in Anthracycline-Induced Cardiotoxicity. Cells 2025; 14:169. [PMID: 39936961 PMCID: PMC11817789 DOI: 10.3390/cells14030169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/27/2024] [Accepted: 11/27/2024] [Indexed: 02/13/2025] Open
Abstract
Anthracyclines are a class of chemotherapeutics commonly used to treat a range of cancers. Despite success in improving cancer survival rates, anthracyclines have dose-limiting cardiotoxicity that prevents more widespread clinical utility. Currently, the therapeutic options for these patients are limited to the iron-chelating agent dexrazoxane, the only FDA-approved drug for anthracycline cardiotoxicity. However, the clinical use of dexrazoxane has failed to replicate expectations from preclinical studies. A limited list of GPCRs have been identified as pathogenic in anthracycline-induced cardiotoxicity, including receptors (frizzled, adrenoreceptors, angiotensin II receptors) previously implicated in cardiac remodeling in other pathologies. The RNA sequencing of iPSC-derived cardiac myocytes from patients has increased our understanding of the pathogenic mechanisms driving cardiotoxicity. These data identified changes in the expression of novel GPCRs, heterotrimeric G proteins, and the regulatory pathways that govern downstream signaling. This review will capitalize on insights from these experiments to explain aspects of disease pathogenesis and cardiac remodeling. These data provide a cornucopia of possible unexplored potential pathways by which we can reduce the cardiotoxic side effects, without compromising the anti-cancer effects, of doxorubicin and provide new therapeutic options to improve the recovery and quality of life for patients undergoing chemotherapy.
Collapse
Affiliation(s)
- Nimish Biswal
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Ritika Harish
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
| | - Minahil Roshan
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Sathvik Samudrala
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Xuanmao Jiao
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
| | - Richard G. Pestell
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
- The Wistar Institute, Philadelphia, PA 19104, USA
| | - Anthony W. Ashton
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
- Division of Perinatal Research, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW 2065, Australia
- Division of Cardiovascular Medicine, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
| |
Collapse
|
|
3
|
Li J, Chen MM, Zhang B, Zhao Y. Integrated bioinformatics analysis reveals that CCBP2 and GPR87 are new GPCR-associated biomarkers for preeclampsia. Reprod Biol Endocrinol 2024; 22:151. [PMID: 39593099 PMCID: PMC11590348 DOI: 10.1186/s12958-024-01324-5] [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: 09/24/2024] [Accepted: 11/19/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Preeclampsia (PE) is a multifaceted pregnancy syndrome marked by multiple system involvement and a significant contributor to maternal mortality. This condition is characterized by a critical lack of early diagnostic measures and viable therapeutic options, underscoring an urgent need for the identification of reliable markers with both diagnostic and therapeutic potential. METHODS This study utilized Weighted Gene Co-expression Network Analysis (WGCNA) to explore the role of G protein-coupled receptors (GPCRs) in the pathogenesis of PE. RESULTS Our analysis pinpointed CCBP2 (ACKR2) and GPR87 as central PE-associated GPCRs. Experimental validation of these findings revealed that both CCBP2 and GPR87 significantly inhibit the proliferation, migration, and invasion of trophoblast cells-core phenomena underlying the pathology of PE. CONCLUSION Thus, our findings add valuable candidates to the growing list of biomarkers for preeclampsia and offer promising targets for future therapeutic development.
Collapse
Affiliation(s)
- Jie Li
- Institute for Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China
- Department of Oncology, Qingdao Cancer Hospital, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao, 266042, China
| | - Meng-Meng Chen
- Key Laboratory of Cancer and Immune Cells of Qingdao, Qingdao, 266021, China
- Qingdao Restore Biotechnology Co., Ltd, Qingdao, 266111, Shandong, P.R. China
| | - Bingqiang Zhang
- Key Laboratory of Cancer and Immune Cells of Qingdao, Qingdao, 266021, China
| | - Yi Zhao
- Institute for Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China.
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250001, China.
| |
Collapse
|
|
4
|
Wang L, Wang M, Tang X, Zhang M, Zhang K, Gao B. Mechanistic Studies of Cyclooxygenase-2 (COX-2) in Skeletal Muscle Cells During Rotator Cuff Injury: An In Vitro Study. Physiol Res 2024; 73:769-778. [PMID: 39545791 PMCID: PMC11629944 DOI: 10.33549/physiolres.935282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 05/15/2024] [Indexed: 12/13/2024] Open
Abstract
The mechanism of rotator cuff injury remains to be elucidated. And COX-2 plays a dual role in skeletal muscle injury and regeneration, would be associated with the development of rotator cuff injury. Therefore, we chose human skeletal muscle cells (HSKMC) as an in vitro muscle tissue model and transfected lentivirus with overexpressed COX-2 to simulate the in vitro environment of rotator cuff injury. To investigate the specific molecular biological mechanism of COX-2, transcriptome sequencing (RNA-Seq) was used to analyze the differentially expressed mRNAs in HSKMC overexpressing COX-2. Enrichment analysis was performed to analyze these differentially expressed genes and real-time quantitative PCR (RT-qPCR) was used to examine the mRNA levels of genes induced by overexpression. Subsequently, the role of COX-2 in cell proliferation was confirmed by cell counting kit-8 (CCK-8), and focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation induced by COX-2 was utilized by western blotting (WB). The results showed that total of 30,759 differentially expressed genes were obtained, and the expression of CYP4F3 and GPR87 was significantly increased. COX-2 could bind CYP4F3 and GPR87 and co-localize with them in the cytoplasm. Finally, COX-2 promoted the proliferation of human skeletal muscle cells by activating the FAK and STAT3 pathways.
Collapse
Affiliation(s)
- L Wang
- Department of Orthopaedics, The First Affiliated Hospital of Ningbo University, Jiangbei District, Ningbo, Zhejiang Province, China.
| | | | | | | | | | | |
Collapse
|
|
5
|
Karalis T, Poulogiannis G. The Emerging Role of LPA as an Oncometabolite. Cells 2024; 13:629. [PMID: 38607068 PMCID: PMC11011573 DOI: 10.3390/cells13070629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/25/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024] Open
Abstract
Lysophosphatidic acid (LPA) is a phospholipid that displays potent signalling activities that are regulated in both an autocrine and paracrine manner. It can be found both extra- and intracellularly, where it interacts with different receptors to activate signalling pathways that regulate a plethora of cellular processes, including mitosis, proliferation and migration. LPA metabolism is complex, and its biosynthesis and catabolism are under tight control to ensure proper LPA levels in the body. In cancer patient specimens, LPA levels are frequently higher compared to those of healthy individuals and often correlate with poor responses and more aggressive disease. Accordingly, LPA, through promoting cancer cell migration and invasion, enhances the metastasis and dissemination of tumour cells. In this review, we summarise the role of LPA in the regulation of critical aspects of tumour biology and further discuss the available pre-clinical and clinical evidence regarding the feasibility and efficacy of targeting LPA metabolism for effective anticancer therapy.
Collapse
Affiliation(s)
| | - George Poulogiannis
- Signalling and Cancer Metabolism Laboratory, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK;
| |
Collapse
|
|
6
|
Chen Y, Huang A, Bi Y, Wei W, Huang Y, Ye Y. Genomic insights and prognostic significance of novel biomarkers in pancreatic ductal adenocarcinoma: A comprehensive analysis. Biochem Biophys Rep 2024; 37:101580. [PMID: 38107664 PMCID: PMC10724495 DOI: 10.1016/j.bbrep.2023.101580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/06/2023] [Accepted: 11/07/2023] [Indexed: 12/19/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly prevalent digestive system malignancy, with a significant impact on public health, especially in the elderly population. The advent of the Human Genome Project has opened new avenues for precision medicine, allowing researchers to explore genetic markers and molecular targets for cancer diagnosis and treatment. Despite significant advances in genomic research, early diagnosis of pancreatic cancer remains elusive due to the lack of highly sensitive and specific markers. Therefore, there is a need for in-depth research to identify more precise and reliable diagnostic markers for pancreatic cancer. In this study, we utilized a combination of public databases from different sources to meticulously screen genes associated with prognosis in pancreatic cancer. We used gene differential analysis, univariate cox regression analysis, least absolute selection and shrinkage operator (LASSO) regression, and multivariate cox regression analysis to identify genes associated with prognosis. Subsequently, we constructed a scoring system, validated its validity using survival analysis and ROC analysis, and further confirmed its reliability by nomogram and decision curve analysis (DCA). We evaluated the diagnostic value of this scoring system for pancreatic cancer prognosis and validated the function of the genes using single cell data analysis. Our analysis identifies six genes, including GABRA3, IL20RB, CDK1, GPR87, TTYH3, and KCNA2, that were strongly associated with PDAC prognosis. Clinical prognostic models based on these genes showed strong predictive power not only in the training set but also in external datasets. Functional enrichment analysis revealed significant differences between high- and low-risk groups mainly in immune-related functions. Additionally, we explored the potential of the risk score as a marker for immunotherapy response and identified key factors within the tumor microenvironment. The single-cell RNA sequencing analysis further enriched our understanding of cell clusters and six hub genes expressions. This comprehensive investigation provides valuable insights into pancreatic PDAC and its intricate immune landscape. The identified genes and their functional significance underscore the importance of continued research into improving diagnosis and treatment strategies for PDAC.
Collapse
Affiliation(s)
- Yuling Chen
- Department of Rheumatology and Immunology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, China
| | - Anle Huang
- Department of Gastrointestinal Oncology Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China, 361001
| | - Yuanjie Bi
- School of Science, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Wei Wei
- Department of Emergency, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, China
| | - Yongsheng Huang
- School of Science, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Yuanchun Ye
- School of Science, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
- Shenzhen Bay Laboratory, Shenzhen, Guangdong Province, China
- Department of Hematology Oncology and Tumor Immunity, Benjamin Franklin Campus, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| |
Collapse
|
|
7
|
Jobe A, Vijayan R. Orphan G protein-coupled receptors: the ongoing search for a home. Front Pharmacol 2024; 15:1349097. [PMID: 38495099 PMCID: PMC10941346 DOI: 10.3389/fphar.2024.1349097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/15/2024] [Indexed: 03/19/2024] Open
Abstract
G protein-coupled receptors (GPCRs) make up the largest receptor superfamily, accounting for 4% of protein-coding genes. Despite the prevalence of such transmembrane receptors, a significant number remain orphans, lacking identified endogenous ligands. Since their conception, the reverse pharmacology approach has been used to characterize such receptors. However, the multifaceted and nuanced nature of GPCR signaling poses a great challenge to their pharmacological elucidation. Considering their therapeutic relevance, the search for native orphan GPCR ligands continues. Despite limited structural input in terms of 3D crystallized structures, with advances in machine-learning approaches, there has been great progress with respect to accurate ligand prediction. Though such an approach proves valuable given that ligand scarcity is the greatest hurdle to orphan GPCR deorphanization, the future pairings of the remaining orphan GPCRs may not necessarily take a one-size-fits-all approach but should be more comprehensive in accounting for numerous nuanced possibilities to cover the full spectrum of GPCR signaling.
Collapse
Affiliation(s)
- Amie Jobe
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ranjit Vijayan
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
- The Big Data Analytics Center, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| |
Collapse
|
|
8
|
Liu Q, Zhou Y, Cogan JD, Mitchell DB, Sheng Q, Zhao S, Bai Y, Ciombor KK, Sabusap CM, Malabanan MM, Markin CR, Douglas K, Ding G, Banovich NE, Nickerson DA, Blue EE, Bamshad MJ, Brown KK, Schwartz DA, Phillips JA, Martinez-Barricarte R, Salisbury ML, Shyr Y, Loyd JE, Kropski JA, Blackwell TS. The Genetic Landscape of Familial Pulmonary Fibrosis. Am J Respir Crit Care Med 2023; 207:1345-1357. [PMID: 36622818 PMCID: PMC10595451 DOI: 10.1164/rccm.202204-0781oc] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 01/09/2023] [Indexed: 01/10/2023] Open
Abstract
Rationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. Measurements and Main Results: It was found that 14.9-23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere-related genes. New candidate genes were identified in a small number of families-including SYDE1, SERPINB8, GPR87, and NETO1-and tools were developed for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.
Collapse
Affiliation(s)
- Qi Liu
- Department of Biostatistics
| | | | - Joy D. Cogan
- Division of Medical Genetics and Genomic Medicine, Department of Pediatrics
| | | | | | | | | | | | | | | | | | | | - Guixiao Ding
- Division of Allergy, Pulmonary and Critical Care Medicine
| | | | | | | | - Michael J. Bamshad
- Department of Genome Sciences
- Brotman-Baty Institute, Seattle, Washington
- Department of Pediatrics, University of Washington, Seattle, Washington
| | | | - David A. Schwartz
- Department of Medicine, School of Medicine, University of Colorado Denver, Denver, Colorado; and
| | - John A. Phillips
- Division of Medical Genetics and Genomic Medicine, Department of Pediatrics
| | | | | | | | - James E. Loyd
- Division of Allergy, Pulmonary and Critical Care Medicine
| | - Jonathan A. Kropski
- Division of Allergy, Pulmonary and Critical Care Medicine
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Timothy S. Blackwell
- Division of Allergy, Pulmonary and Critical Care Medicine
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| |
Collapse
|
|
9
|
Wang Y, Qi Z, Li Z, Bai S, Damirin A. LPAR2-mediated action promotes human renal cell carcinoma via MAPK/NF-κB signaling to regulate cytokine network. J Cancer Res Clin Oncol 2022; 149:2041-2055. [PMID: 35857125 DOI: 10.1007/s00432-022-04197-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/07/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE Lysophosphatidic acid (LPA) exerts various physiological and pathological effects by activating its distinct G-protein-coupled LPA receptors. We demonstrated that LPA can increase the migration and proliferation of renal carcinoma cells. Meanwhile, LPAR1 and LPAR2 were preferentially expressed in renal cancer (RC) cell lines. So, the study aimed to determine the LPA receptor subtypes involved in LPA-induced actions and whether they could be used as a precision therapeutic target for renal cancer. METHODS Biological approaches combined with big data analysis were used to demonstrate the role of LPAR2 in the progression of renal cancer. RESULTS We found that the proliferation, clone formation, and migration in response to LPA were enhanced in LPAR2-overexpressing renal cancer cells, whereas, the actions were suppressed by LPAR2 antagonist in the cells. LPAR2 has also shown clinical diagnostic and prognostic value in renal carcinoma based on bioinformatics analysis and clinical tissue microarray analysis. In vivo study shown that tumor growth and metastasis were significantly increased in the LPAR2-overexpressing cells-derived solid tumors. LPA stimulated MAPK and NF-κB activation, and LPA-induced actions were inhibited by MAPKs and NF-κB inhibitors, respectively. Subsequently, the transcriptomic results revealed that LPAR2 strongly affected the cytokines production, and the increased IL6, CXCL8, and TNF were confirmed again using Kit assay. CONCLUSIONS We have identified that LPAR2 is critical for LPA-promoted renal cancer progression, and the actions mainly dependent the MAPK and NF-κB activation mechanism. Then, the expression of inflammatory factors activated by NF-κB is also suspected to be involved in LPAR2-mediated carcinogenesis. Thus, LPAR2 may be a promising therapeutic target for renal cancer.
Collapse
Affiliation(s)
- Yuewu Wang
- School of Life Sciences, Inner Mongolia University, Hohhot, 010110, Inner Mongolia, China.,College of Pharmacy, Inner Mongolia Medical University, Hohhot, 010110, Inner Mongolia, China
| | - Zhimin Qi
- School of Life Sciences, Inner Mongolia University, Hohhot, 010110, Inner Mongolia, China
| | - Ze Li
- School of Life Sciences, Inner Mongolia University, Hohhot, 010110, Inner Mongolia, China
| | - Shuyu Bai
- School of Life Sciences, Inner Mongolia University, Hohhot, 010110, Inner Mongolia, China
| | - Alatangaole Damirin
- School of Life Sciences, Inner Mongolia University, Hohhot, 010110, Inner Mongolia, China.
| |
Collapse
|
|
10
|
Heinzelmann K, Hu Q, Hu Y, Dobrinskikh E, Ansari M, Melo-Narváez MC, Ulke HM, Leavitt C, Mirita C, Trudeau T, Saal ML, Rice P, Gao B, Janssen WJ, Yang IV, Schiller HB, Vladar EK, Lehmann M, Königshoff M. Single-cell RNA sequencing identifies G-protein coupled receptor 87 as a basal cell marker expressed in distal honeycomb cysts in idiopathic pulmonary fibrosis. Eur Respir J 2022; 59:2102373. [PMID: 35604813 PMCID: PMC9203838 DOI: 10.1183/13993003.02373-2021] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 03/02/2022] [Indexed: 11/15/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating and life-threatening lung disease characterised by epithelial reprogramming and increased extracellular matrix deposition leading to loss of lung function. Prominent histopathological structures in the distal IPF lung include honeycomb cysts in the alveolar space [1]. These are heterogeneous bronchiolised areas that feature clusters of simple epithelium with keratin (KRT)5+ basal-like cells interspersed with pseudostratified epithelium containing differentiated, hyperplastic epithelial cells, as well as aberrant ciliated cells [2–5]. Recent single-cell RNA sequencing studies of whole lungs from IPF and donor tissue revealed cellular subtypes unique to IPF, including basaloid KRT5−/KRT17+ cells present in the distal lung [6–10]. Bronchiolisation and honeycombing are features of IPF. ScRNA sequencing identified GPR87 as a novel marker of basal cells in IPF, enriched in honeycomb cysts. GPR87 overexpression resulted in aberrant airway cell differentiation. https://bit.ly/3i4dXeT
Collapse
Affiliation(s)
- Katharina Heinzelmann
- Institute of Lung Health and Immunity, Comprehensive Pneumology Center Munich, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
- K. Heinzelmann and Q. Hu contributed equally
| | - Qianjiang Hu
- Institute of Lung Health and Immunity, Comprehensive Pneumology Center Munich, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- K. Heinzelmann and Q. Hu contributed equally
| | - Yan Hu
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Evgenia Dobrinskikh
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Meshal Ansari
- Institute of Lung Health and Immunity, Comprehensive Pneumology Center Munich, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - M Camila Melo-Narváez
- Institute of Lung Health and Immunity, Comprehensive Pneumology Center Munich, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Henrik M Ulke
- Institute of Lung Health and Immunity, Comprehensive Pneumology Center Munich, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Colton Leavitt
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Carol Mirita
- Eastern Colorado VA Healthcare System, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
| | - Tammy Trudeau
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Maxwell L Saal
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Pamela Rice
- Eastern Colorado VA Healthcare System, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
| | - Bifeng Gao
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - William J Janssen
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
- Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine, National Jewish Health, Denver, CO, USA
| | - Ivana V Yang
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Herbert B Schiller
- Institute of Lung Health and Immunity, Comprehensive Pneumology Center Munich, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Eszter K Vladar
- Dept of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
- Dept of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mareike Lehmann
- Institute of Lung Health and Immunity, Comprehensive Pneumology Center Munich, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
- M. Lehmann and M. Königshoff contributed equally to this article as lead authors and supervised the work
| | - Melanie Königshoff
- Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- M. Lehmann and M. Königshoff contributed equally to this article as lead authors and supervised the work
| |
Collapse
|
|
11
|
GPR87 Promotes Metastasis through the AKT-eNOS-NO Axis in Lung Adenocarcinoma. Cancers (Basel) 2021; 14:cancers14010019. [PMID: 35008182 PMCID: PMC8750422 DOI: 10.3390/cancers14010019] [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: 11/17/2021] [Revised: 12/17/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
Lung adenocarcinoma is one of the leading causes of cancer-related deaths. Despite the availability of advanced anticancer drugs for lung cancer treatment, the prognosis of patients still remains poor. There is a need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. The functional experiments in vitro and in vivo were performed to evaluate the role of GPR87 expression on lung adenocarcinoma metastasis. The public lung adenocarcinoma dataset was used to determine the clinical relevance of GPR87 expression in patients with lung adenocarcinoma. GPR87 is upregulated in various cancer; however, the biological function of GPR87 has not yet been established in lung adenocarcinoma. In this study, we found that GPR87 expression is upregulated in lung adenocarcinoma and is associated with poor patient prognosis. Additionally, we showed that GPR87 overexpression promotes invasiveness and metastasis of lung adenocarcinoma cells. Furthermore, we demonstrated that AKT-eNOS-NO signaling is a novel downstream pathway of GPR87 in lung adenocarcinoma. Conversely, we confirmed that silencing of GPR87 expression suppressed these phenotypes. Our results reveal the oncogenic function of GPR87 in cancer progression and metastasis through the activation of eNOS as a key mediator. Therefore, we propose that targeting eNOS could be a novel therapeutic strategy to improve the clinical treatment of lung adenocarcinoma.
Collapse
|
|
12
|
Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special? Cells 2021; 10:cells10082059. [PMID: 34440828 PMCID: PMC8394178 DOI: 10.3390/cells10082059] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/13/2022] Open
Abstract
Lysophosphatidic acid (LPA) refers to a family of simple phospholipids that act as ligands for G protein-coupled receptors. While LPA exerts effects throughout the body in normal physiological circumstances, its pathological role in cancer is of great interest from a therapeutic viewpoint. The numerous LPA receptors (LPARs) are coupled to a variety of G proteins, and more than one LPAR is typically expressed on any given cell. While the individual receptors signal through conventional GPCR pathways, LPA is particularly efficacious in stimulating cancer cell proliferation and migration. This review addresses the mechanistic aspects underlying these pro-tumorigenic effects. We provide examples of LPA signaling responses in various types of cancers, with an emphasis on those where roles have been identified for specific LPARs. While providing an overview of LPAR signaling, these examples also reveal gaps in our knowledge regarding the mechanisms of LPA action at the receptor level. The current understanding of the LPAR structure and the roles of LPAR interactions with other receptors are discussed. Overall, LPARs provide insight into the potential molecular mechanisms that underlie the ability of individual GPCRs (or combinations of GPCRs) to elicit a unique spectrum of responses from their agonist ligands. Further knowledge of these mechanisms will inform drug discovery, since GPCRs are promising therapeutic targets for cancer.
Collapse
|
|
13
|
Yasui H, Nishinaga Y, Taki S, Takahashi K, Isobe Y, Shimizu M, Koike C, Taki T, Sakamoto A, Katsumi K, Ishii K, Sato K. Near-infrared photoimmunotherapy targeting GPR87: Development of a humanised anti-GPR87 mAb and therapeutic efficacy on a lung cancer mouse model. EBioMedicine 2021; 67:103372. [PMID: 33993055 PMCID: PMC8138482 DOI: 10.1016/j.ebiom.2021.103372] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/25/2021] [Accepted: 04/16/2021] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND GPR87 is a G-protein receptor that is specifically expressed in tumour cells, such as lung cancer, and rarely expressed in normal cells. GPR87 is a promising target for cancer therapy, but its ligand is controversial. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy in which a photosensitiser, IRDye700DX (IR700), binds to antibodies and specifically destroys target cells by irradiating them with near-infrared-light. Here, we aimed to develop a NIR-PIT targeting GPR87. METHODS We evaluated the expression of GPR87 in resected specimens of lung cancer and malignant pleural mesothelioma (MPM) resected at Nagoya University Hospital using immunostaining. Humanised anti-GPR87 antibody (huGPR87) was generated by introducing CDRs from mouse anti-GPR87 antibody generated by standard hybridoma method. HuGPR87 was conjugated with IR700 and the therapeutic effect of NIR-PIT was evaluated in vitro and in vivo using lung cancer or MPM cell lines. FINDINGS Among the surgical specimens, 54% of lung cancer and 100% of MPM showed high expression of GPR87. It showed therapeutic effects on lung cancer and MPM cell lines in vitro, and showed therapeutic effects in multiple models in vivo. INTERPRETATION These results suggest that NIR-PIT targeting GPR87 is a promising therapeutic approach for the treatment of thoracic cancer. FUNDING This research was supported by the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217, JSPS), FOREST-Souhatsu, CREST (JST).
Collapse
Affiliation(s)
- Hirotoshi Yasui
- Respiratory Medicine, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Yuko Nishinaga
- Respiratory Medicine, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Shunichi Taki
- Respiratory Medicine, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Kazuomi Takahashi
- Respiratory Medicine, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Yoshitaka Isobe
- Respiratory Medicine, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Misae Shimizu
- Nagoya University Institute for Advanced Research, Advanced Analytical and Diagnostic Imaging Center (AADIC) / Medical Engineering Unit (MEU), B3 Unit, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Chiaki Koike
- Nagoya University Institute for Advanced Research, Advanced Analytical and Diagnostic Imaging Center (AADIC) / Medical Engineering Unit (MEU), B3 Unit, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Tetsuro Taki
- Department of Pathology, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan
| | - Aya Sakamoto
- Perseus Proteomics, Inc., 4-7-6, Komaba 153-0041, Meguro-ku, Tokyo, Japan
| | - Keiko Katsumi
- Perseus Proteomics, Inc., 4-7-6, Komaba 153-0041, Meguro-ku, Tokyo, Japan
| | - Keisuke Ishii
- Perseus Proteomics, Inc., 4-7-6, Komaba 153-0041, Meguro-ku, Tokyo, Japan
| | - Kazuhide Sato
- Respiratory Medicine, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan; Nagoya University Institute for Advanced Research, Advanced Analytical and Diagnostic Imaging Center (AADIC) / Medical Engineering Unit (MEU), B3 Unit, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan; FOREST- Souhatsu, CREST, JST; Nagoya University Institute for Advanced Research, S-YLC, Furo-cho, Chikusa-ku, Nagoya 464-8601, Aichi,, Japan.
| |
Collapse
|
|
14
|
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.
Collapse
Affiliation(s)
- Eric Birgbauer
- Department of Biology, Winthrop University, Rock Hill, SC, USA.
| |
Collapse
|
|
15
|
Geraldo LHM, Spohr TCLDS, Amaral RFD, Fonseca ACCD, Garcia C, Mendes FDA, Freitas C, dosSantos MF, Lima FRS. Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies. Signal Transduct Target Ther 2021; 6:45. [PMID: 33526777 PMCID: PMC7851145 DOI: 10.1038/s41392-020-00367-5] [Citation(s) in RCA: 169] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.
Collapse
Affiliation(s)
- Luiz Henrique Medeiros Geraldo
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | | | | | | | - Celina Garcia
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fabio de Almeida Mendes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Catarina Freitas
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcos Fabio dosSantos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Flavia Regina Souza Lima
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
| |
Collapse
|
|
16
|
Mita M, Matsubara S, Osugi T, Shiraishi A, Wada A, Satake H. A novel G protein-coupled receptor for starfish gonadotropic hormone, relaxin-like gonad-stimulating peptide. PLoS One 2020; 15:e0242877. [PMID: 33226996 PMCID: PMC7682835 DOI: 10.1371/journal.pone.0242877] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Gonadotropic hormones play important regulatory roles in reproduction. Relaxin-like gonad-stimulating peptide (RGP) is a gonadotropin-like hormone in starfish. However, a receptor for RGP remains to be identified. Here, we describe the identification of an authentic receptor for RGP (RGPR) in the starfish, Patiria pectinifera. A binding assay using radioiodinated P. pectinifera RGP (PpeRGP) revealed that RGPR was expressed in ovarian follicle cells. A RGPR candidate was identified by homology-searching of transcriptome data of P. pectinifera follicle cells. Based on the contig sequences, a putative 947-amino acid PpeRGPR was cloned from follicle cells. Like the vertebrate relaxin family peptide receptors (RXFP 1 and 2), PpeRGPR was a G protein-coupled receptor that harbored a low-density lipoprotein-receptor class A motif and leucine-rich repeat sequences in the extracellular domain of the N-terminal region. Sf9 cells transfected with Gαq16-fused PpeRGPR activated calcium ion mobilization in response to PpeRGP, but not to RGP of another starfish Asterias amurensis, in a dose-dependent fashion. These results confirmed the species-specific reactivity of RGP and the cognate receptor. Thus, the present study provides evidence that PpeRGPR is a specific receptor for PpeRGP. To the best of our knowledge, this is the first report on the identification of a receptor for echinoderm RGP.
Collapse
Affiliation(s)
- Masatoshi Mita
- Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
| | - Shin Matsubara
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Tomohiro Osugi
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Akira Shiraishi
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Azumi Wada
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Honoo Satake
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| |
Collapse
|
|
17
|
Communi D, Horckmans M, Boeynaems JM. P2Y 4, P2Y 6 and P2Y 11 receptors: From the early days of cloning to their function. Biochem Pharmacol 2020; 187:114347. [PMID: 33232731 DOI: 10.1016/j.bcp.2020.114347] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/19/2020] [Accepted: 11/19/2020] [Indexed: 02/01/2023]
Abstract
The family of P2Y nucleotide receptors is composed of eight members differentiated by their pharmacology and their coupling to specific G-proteins and transduction mechanisms. The laboratory studying these nucleotide receptors at IRIBHM institute (Free University of Brussels) has participated actively in their cloning. We used classical cloning by homology strategies relying on polymerase chain reactions with degenerate primers or on DNA libraries screening with P2Y receptors-related primers or probes, respectively. We identified and characterised four of the eight human P2Y receptors cloned so far: P2Y4, P2Y6, P2Y11 and P2Y13 receptors. These human receptors displayed specific features in terms of pharmacology such as affinity for pyrimidine nucleotides for P2Y4 and P2Y6 receptors and differential G-protein coupling. Their specific and restricted tissue distribution compared to ubiquitous P2Y1 and P2Y2 receptors led us to study their physiological role in chosen cell systems or using mice deficient for these P2Y subtypes. These studies revealed over the years that the P2Y11 receptor was able to confer tolerogenic and tumorigenic properties to human dendritic cells and that P2Y4 and P2Y6 receptors were involved in mouse heart post-natal development and cardioprotection. P2Y receptors and their identified target genes could constitute therapeutic targets to regulate cardiac hypertrophy and regeneration. The multiple roles of P2Y receptors identified in the ischemic heart and cardiac adipose tissue could have multiple innovative clinical applications and present a major interest in the field of cardiovascular diseases. P2Y receptors can induce cardioprotection by the regulation of cardiac inflammation and the modulation of the volume and composition of cardiac adipose tissue. These findings might lead to the pre-clinical validation of P2Y receptors as new targets for the treatment of myocardial ischemia.
Collapse
Affiliation(s)
- Didier Communi
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
| | - Michael Horckmans
- Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Brussels, Belgium
| | | |
Collapse
|
|
18
|
Mizuno H, Kihara Y. Druggable Lipid GPCRs: Past, Present, and Prospects. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1274:223-258. [PMID: 32894513 DOI: 10.1007/978-3-030-50621-6_10] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
G protein-coupled receptors (GPCRs) have seven transmembrane spanning domains and comprise the largest superfamily with ~800 receptors in humans. GPCRs are attractive targets for drug discovery because they transduce intracellular signaling in response to endogenous ligands via heterotrimeric G proteins or arrestins, resulting in a wide variety of physiological and pathophysiological responses. The endogenous ligands for GPCRs are highly chemically diverse and include ions, biogenic amines, nucleotides, peptides, and lipids. In this review, we follow the KonMari method to better understand druggable lipid GPCRs. First, we have a comprehensive tidying up of lipid GPCRs including receptors for prostanoids, leukotrienes, specialized pro-resolving mediators (SPMs), lysophospholipids, sphingosine 1-phosphate (S1P), cannabinoids, platelet-activating factor (PAF), free fatty acids (FFAs), and sterols. This tidying up consolidates 46 lipid GPCRs and declutters several perplexing lipid GPCRs. Then, we further tidy up the lipid GPCR-directed drugs from the literature and databases, which identified 24 clinical drugs targeting 16 unique lipid GPCRs available in the market and 44 drugs under evaluation in more than 100 clinical trials as of 2019. Finally, we introduce drug designs for GPCRs that spark joy, such as positive or negative allosteric modulators (PAM or NAM), biased agonism, functional antagonism like fingolimod, and monoclonal antibodies (MAbs). These strategic drug designs may increase the efficacy and specificity of drugs and reduce side effects. Technological advances will help to discover more endogenous lipid ligands from the vast number of remaining orphan GPCRs and will also lead to the development novel lipid GPCR drugs to treat various diseases.
Collapse
Affiliation(s)
| | - Yasuyuki Kihara
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
| |
Collapse
|
|
19
|
Yu M, Wang Y, Li P, Li M, Gao X. Taurine attenuates gossypol-induced apoptosis of C2C12 mouse myoblasts via the GPR87-AMPK/AKT signaling. Amino Acids 2020; 52:1285-1298. [PMID: 32918616 DOI: 10.1007/s00726-020-02888-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 09/05/2020] [Indexed: 12/24/2022]
Abstract
Gossypol, a toxic polyphenol extracted from cotton seeds, is hazardous to human and animal health. Taurine is considered as an essential or semi-essential amino acid and has diverse cytoprotective effects. This study was aimed to investigate the protective effect and molecular mechanism of taurine against apoptosis of C2C12 mouse myoblasts induced by gossypol. C2C12 mouse myoblasts were exposed to gossypol (0, 1 nM, 10 nM, 100 nM, 1 μM, and 10 μM). Cell numbers were rapidly decreased with increasing concentrations of gossypol. Gossypol significantly induced apoptosis, decreased Bcl2 expression, and increased the protein levels of Bax and the cleaved caspase 3. Taurine (0.24 mM) treatment largely rescued the cell number decreased by gossypol, attenuated gossypol-induced cell apoptosis. GPR87 knockdown abolished the inhibition by taurine of cell apoptosis. Furthermore, GPR87 overexpression attenuated cell apoptosis induced by gossypol. Both taurine treatment and GPR87 overexpression stimulated AKT phosphorylation but inhibited AMPK phosphorylation, whereas gossypol had the opposite effects. Taurine treatment promoted GPR87 expression and subcellular localization and partially rescued the inhibition of gossypol on this expression. In summary, these data reveal that taurine attenuates gossypol-induced apoptosis of C2C12 mouse myoblasts via the GPR87-AMPK/AKT signaling.
Collapse
Affiliation(s)
- Mengmeng Yu
- College of Animal Science, Yangtze University, Jingzhou, 434020, China
| | - Yang Wang
- College of Animal Science, Yangtze University, Jingzhou, 434020, China
| | - Ping Li
- College of Animal Science, Yangtze University, Jingzhou, 434020, China
| | - Meng Li
- College of Animal Science, Yangtze University, Jingzhou, 434020, China
| | - Xuejun Gao
- College of Animal Science, Yangtze University, Jingzhou, 434020, China.
| |
Collapse
|
|
20
|
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.
Collapse
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.
| |
Collapse
|
|
21
|
Ma S, Yeom J, Lim YH. Exogenous NAD + Stimulates MUC2 Expression in LS 174T Goblet Cells via the PLC-Delta/PTGES/PKC-Delta/ERK/CREB Signaling Pathway. Biomolecules 2020; 10:E580. [PMID: 32283838 PMCID: PMC7226023 DOI: 10.3390/biom10040580] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND MUC2, a major component of the mucus layer in the intestine, is associated with antimicrobial activity and gut immune system function. Currently, mucin is mainly known for its critical function in defense against toxic molecules and pathogens. In this study, we investigated the stimulatory effects of exogenous nicotinamide adenine dinucleotide (NAD+) on the expression of MUC2 in LS 174T goblet cells. METHODS Genes related to MUC2 synthesis were measured by quantitative real-time PCR (qPCR). To analyze the gene expression profiles of NAD+-treated LS 174T goblet cells, RNA sequencing was performed. MUC2 expression in the cells and secreted MUC2 were measured by immunocytochemistry (ICC) and ELISA, respectively. RESULTS NAD+ significantly stimulated MUC2 expression at mRNA and protein levels and increased the secretion of MUC2. Through RNA sequencing, we found that the expression of genes involved in arachidonic acid metabolism increased in NAD+-treated cells compared with the negative control cells. NAD+ treatment increased phospholipase C (PLC)-δ and prostaglandin E synthase (PTGES) expression, which was inhibited by the appropriate inhibitors. Among the protein kinase C (PKC) isozymes, PKC-δ was involved in the increase in MUC2 expression. In addition, extracellular signal-regulated kinase (ERK)1/2 and cyclic AMP (cAMP) response element-binding protein (CREB) transcript levels were higher in NAD+-treated cells than in the negative control cells, and the enhanced levels of phosphorylated CREB augmented MUC2 expression. CONCLUSIONS Exogenous NAD+ increases MUC2 expression by stimulating the PLC-δ/PTGES/PKC-δ/ERK/CREB signaling pathway.
Collapse
Affiliation(s)
- Seongho Ma
- Department of Integrated Biomedical and Life Sciences, Graduate School, Korea University, Seoul 02841, Korea; (S.M.); (J.Y.)
| | - Jiah Yeom
- Department of Integrated Biomedical and Life Sciences, Graduate School, Korea University, Seoul 02841, Korea; (S.M.); (J.Y.)
| | - Young-Hee Lim
- Department of Integrated Biomedical and Life Sciences, Graduate School, Korea University, Seoul 02841, Korea; (S.M.); (J.Y.)
- Department of Public Health Science (Brain Korea 21 PLUS program), Graduate School, Korea University, Seoul 02841, Korea
- Department of Laboratory Medicine, Korea University Guro Hospital, Seoul 08308, Korea
| |
Collapse
|
|
22
|
Luo C, Yu M, Li S, Huang X, Qi H, Gao X. Methionine stimulates GlyRS phosphorylation via the GPR87-CDC42/Rac1-MAP3K10 signaling pathway. Biochem Biophys Res Commun 2020; 523:847-852. [PMID: 31954518 DOI: 10.1016/j.bbrc.2019.12.124] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 12/24/2019] [Indexed: 02/08/2023]
|
|
23
|
Abstract
As basic research into GPCR signaling and its association with disease has come into fruition, greater clarity has emerged with regards to how these receptors may be amenable to therapeutic intervention. As a diverse group of receptor proteins, which regulate a variety of intracellular signaling pathways, research in this area has been slow to yield tangible therapeutic agents for the treatment of a number of diseases including cancer. However, recently such research has gained momentum based on a series of studies that have sought to define GPCR proteins dynamics through the elucidation of their crystal structures. In this chapter, we define the approaches that have been adopted in developing better therapeutics directed against the specific parts of the receptor proteins, such as the extracellular and the intracellular domains, including the ligands and auxiliary proteins that bind them. Finally, we also briefly outline how GPCR-derived signaling transduction pathways hold great potential as additional targets.
Collapse
Affiliation(s)
- Surinder M Soond
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation.
| | - Andrey A Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation.
| |
Collapse
|
|
24
|
Abstract
Lysophosphatidic acid (LPA) is an endogenous cell signaling molecule, and dysregulation of LPA signaling pathways is accompanied by several types of cancer. Herein, we developed a chemical proteomic method for the proteome-wide identification of LPA-binding proteins. The method involves the synthesis of a desthiobiotin-conjugated LPA acyl phosphate probe for the covalent labeling, enrichment, and subsequent LC-MS/MS identification of LPA-binding proteins at the proteome-wide level. By conducting labeling reactions at two different probe concentrations (10 and 100 μM) in conjunction with an SILAC (stable isotope labeling by amino acids in cell culture)-based workflow, we characterized the LPA-binding capabilities of these proteins at the entire proteome scale, which led to the identification of 86 candidate LPA-binding proteins in HEK293T cells. Moreover, we validated that two of these proteins, annexin A5 and phosphoglycerate kinase 1, can bind directly with LPA. Together, we developed a novel LPA probe for the identification and characterizations of LPA-binding proteins from the entire human proteome. The method should be adaptable for the identification of other lipid-binding proteins.
Collapse
Affiliation(s)
- Xuejiao Dong
- Department of Chemistry, University of California, Riverside, California 92521, United States
| | - Linfeng Gao
- Environmental Toxicology Graduate Program, University of California, Riverside, California 92521, United States
| | - Jikui Song
- Environmental Toxicology Graduate Program, University of California, Riverside, California 92521, United States
- Department of Biochemistry, University of California, Riverside, California 92521, United States
| | - Yinsheng Wang
- Department of Chemistry, University of California, Riverside, California 92521, United States
- Environmental Toxicology Graduate Program, University of California, Riverside, California 92521, United States
| |
Collapse
|
|
25
|
Zhou Y, Little PJ, Ta HT, Xu S, Kamato D. Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease. Pharmacol Ther 2019; 204:107404. [DOI: 10.1016/j.pharmthera.2019.107404] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023]
|
|
26
|
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.
Collapse
|
|
27
|
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.
Collapse
Affiliation(s)
- Yan Xu
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut Street R2-E380, Indianapolis, IN 46202, USA.
| |
Collapse
|
|
28
|
MicroRNA Regulation of the Autotaxin-Lysophosphatidic Acid Signaling Axis. Cancers (Basel) 2019; 11:cancers11091369. [PMID: 31540086 PMCID: PMC6770380 DOI: 10.3390/cancers11091369] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/18/2022] Open
Abstract
The revelation that microRNAs (miRNAs) exist within the human genome uncovered an underappreciated mechanism of gene expression. For cells to regulate expression of their genes, miRNA molecules and argonaute proteins bind to mRNAs and interfere with efficient translation of the RNA transcript. Although miRNAs have important roles in normal tissues, miRNAs may adopt aberrant functions in malignant cells depending on their classification as either a tumor suppressor or oncogenic miRNA. Within this review, the current status of miRNA regulation is described in the context of signaling through the lysophosphatidic acid receptors, including the lysophosphatidic acid-producing enzyme, autotaxin. Thus far, research has revealed miRNAs that increase in response to lysophosphatidic acid stimulation, such as miR-21, miR-30c-2-3p, and miR-122. Other miRNAs inhibit the translation of lysophosphatidic acid receptors, such as miR-15b, miR-23a, and miR200c, or proteins that are downstream of lysophosphatidic acid signaling, such as miR-146 and miR-21. With thousands of miRNAs still uncharacterized, it is anticipated that the complex regulation of lysophosphatidic acid signaling by miRNAs will continue to be elucidated. RNA-based therapeutics have entered the clinic with enormous potential in precision medicine. This exciting field is rapidly emerging and it will be fascinating to witness its expansion in scope.
Collapse
|
|
29
|
Ciesielska A, Hromada-Judycka A, Ziemlińska E, Kwiatkowska K. Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS. J Leukoc Biol 2019; 106:1285-1301. [PMID: 31335985 DOI: 10.1002/jlb.2a0918-368rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 06/19/2019] [Accepted: 06/28/2019] [Indexed: 12/15/2022] Open
Abstract
Bacterial LPS strongly induces pro-inflammatory responses of Mϕs after binding to CD14 protein and the TLR4/MD-2 receptor complex. The LPS-triggered signaling can be modulated by extracellular lysophosphatidic acid (LPA), which is of substantial importance for Mϕ functioning under specific pathophysiological conditions, such as atherosclerosis. The molecular mechanisms of the crosstalk between the LPS- and LPA-induced signaling, and the LPA receptors involved, are poorly known. In this report, we show that LPA strongly inhibits the LPS-induced TNF-α production at the mRNA and protein levels in primary Mϕs and Mϕ-like J774 cells. The decreased TNF-α production in LPA/LPS-stimulated cells is to high extent independent of NF-κB but is preceded by enhanced expression and secretion of the anti-inflammatory cytokine IL-10. The IL-10 elevation and TNF-α reduction are both abrogated upon depletion of the LPA5 and LPA6 receptors in J774 cells and can be linked with LPA-mediated activation of p38. We propose that the binding of LPA to LPA5 and LPA6 fine-tunes the LPS-induced inflammatory response by activating p38, and up-regulating IL-10 and down-regulating TNF-α production.
Collapse
Affiliation(s)
- Anna Ciesielska
- Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Aneta Hromada-Judycka
- Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Ewelina Ziemlińska
- Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Katarzyna Kwiatkowska
- Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| |
Collapse
|
|
30
|
Lysophosphatidic Acid and Autotaxin-associated Effects on the Initiation and Progression of Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11070958. [PMID: 31323936 PMCID: PMC6678549 DOI: 10.3390/cancers11070958] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/04/2019] [Accepted: 07/08/2019] [Indexed: 02/07/2023] Open
Abstract
The intestinal epithelium interacts dynamically with the immune system to maintain its barrier function to protect the host, while performing the physiological roles in absorption of nutrients, electrolytes, water and minerals. The importance of lysophosphatidic acid (LPA) and its receptors in the gut has been progressively appreciated. LPA signaling modulates cell proliferation, invasion, adhesion, angiogenesis, and survival that can promote cancer growth and metastasis. These effects are equally important for the maintenance of the epithelial barrier in the gut, which forms the first line of defense against the milieu of potentially pathogenic stimuli. This review focuses on the LPA-mediated signaling that potentially contributes to inflammation and tumor formation in the gastrointestinal tract.
Collapse
|
|
31
|
Tabbai S, Moreno-Fernández RD, Zambrana-Infantes E, Nieto-Quero A, Chun J, García-Fernández M, Estivill-Torrús G, Rodríguez de Fonseca F, Santín LJ, Oliveira TG, Pérez-Martín M, Pedraza C. Effects of the LPA 1 Receptor Deficiency and Stress on the Hippocampal LPA Species in Mice. Front Mol Neurosci 2019; 12:146. [PMID: 31244601 PMCID: PMC6580287 DOI: 10.3389/fnmol.2019.00146] [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: 12/21/2018] [Accepted: 05/17/2019] [Indexed: 12/29/2022] Open
Abstract
Lysophosphatidic acid (LPA) is an important bioactive lipid species that functions in intracellular signaling through six characterized G protein-coupled receptors (LPA1-6). Among these receptors, LPA1 is a strong candidate to mediate the central effects of LPA on emotion and may be involved in promoting normal emotional behaviors. Alterations in this receptor may induce vulnerability to stress and predispose an individual to a psychopathological disease. In fact, mice lacking the LPA1 receptor exhibit emotional dysregulation and cognitive alterations in hippocampus-dependent tasks. Moreover, the loss of this receptor results in a phenotype of low resilience with dysfunctional coping in response to stress and induces anxiety and several behavioral and neurobiological changes that are strongly correlated with mood disorders. In fact, our group proposes that maLPA1-null mice represent an animal model of anxious depression. However, despite the key role of the LPA-LPA1-pathway in emotion and stress coping behaviors, the available information describing the mechanisms by which the LPA-LPA1-pathway regulates emotion is currently insufficient. Because activation of LPA1 requires LPA, here, we used a Matrix-Assisted Laser Desorption/ Ionization mass spectrometry-based approach to evaluate the effects of an LPA1 receptor deficiency on the hippocampal levels of LPA species. Additionally, the impact of stress on the LPA profile was also examined in both wild-type (WT) and the Malaga variant of LPA1-null mice (maLPA1-null mice). Mice lacking LPA1 did not exhibit gross perturbations in the hippocampal LPA species, but the LPA profile was modified, showing an altered relative abundance of 18:0 LPA. Regardless of the genotype, restraint stress produced profound changes in all LPA species examined, revealing that hippocampal LPA species are a key target of stress. Finally, the relationship between the hippocampal levels of LPA species and performance in the elevated plus maze was established. To our knowledge, this study is the first to detect, identify and profile LPA species in the hippocampus of both LPA1-receptor null mice and WT mice at baseline and after acute stress, as well as to link these LPA species with anxiety-like behaviors. In conclusion, the hippocampal LPA species are a key target of stress and may be involved in psychopathological conditions.
Collapse
Affiliation(s)
- Sara Tabbai
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Román Dario Moreno-Fernández
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Emma Zambrana-Infantes
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Andrea Nieto-Quero
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Maria García-Fernández
- Departamento de Fisiología y Medicina Deportiva, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Guillermo Estivill-Torrús
- Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Fernando Rodríguez de Fonseca
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Luis Javier Santín
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Tiago Gil Oliveira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
| | - Margarita Pérez-Martín
- Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Carmen Pedraza
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| |
Collapse
|
|
32
|
Abstract
Neuropeptides play pivotal roles in various biological events in the nervous, neuroendocrine, and endocrine systems, and are correlated with both physiological functions and unique behavioral traits of animals. Elucidation of functional interaction between neuropeptides and receptors is a crucial step for the verification of their biological roles and evolutionary processes. However, most receptors for novel peptides remain to be identified. Here, we show the identification of multiple G protein-coupled receptors (GPCRs) for species-specific neuropeptides of the vertebrate sister group, Ciona intestinalis Type A, by combining machine learning and experimental validation. We developed an original peptide descriptor-incorporated support vector machine and used it to predict 22 neuropeptide-GPCR pairs. Of note, signaling assays of the predicted pairs identified 1 homologous and 11 Ciona-specific neuropeptide-GPCR pairs for a 41% hit rate: the respective GPCRs for Ci-GALP, Ci-NTLP-2, Ci-LF-1, Ci-LF-2, Ci-LF-5, Ci-LF-6, Ci-LF-7, Ci-LF-8, Ci-YFV-1, and Ci-YFV-3. Interestingly, molecular phylogenetic tree analysis revealed that these receptors, excluding the Ci-GALP receptor, were evolutionarily unrelated to any other known peptide GPCRs, confirming that these GPCRs constitute unprecedented neuropeptide receptor clusters. Altogether, these results verified the neuropeptide-GPCR pairs in the protochordate and evolutionary lineages of neuropeptide GPCRs, and pave the way for investigating the endogenous roles of novel neuropeptides in the closest relatives of vertebrates and the evolutionary processes of neuropeptidergic systems throughout chordates. In addition, the present study also indicates the versatility of the machine-learning-assisted strategy for the identification of novel peptide-receptor pairs in various organisms.
Collapse
|
|
33
|
Suckau O, Gross I, Schrötter S, Yang F, Luo J, Wree A, Chun J, Baska D, Baumgart J, Kano K, Aoki J, Bräuer AU. LPA 1 , LPA 2 , LPA 4 , and LPA 6 receptor expression during mouse brain development. Dev Dyn 2019; 248:375-395. [PMID: 30847983 PMCID: PMC6593976 DOI: 10.1002/dvdy.23] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 02/27/2019] [Accepted: 03/02/2019] [Indexed: 12/17/2022] Open
Abstract
Background LPA is a small bioactive phospholipid that acts as an extracellular signaling molecule and is involved in cellular processes, including cell proliferation, migration, and differentiation. LPA acts by binding and activating at least six known G protein–coupled receptors: LPA1–6. In recent years, LPA has been suggested to play an important role both in normal neuronal development and under pathological conditions in the nervous system. Results We show the expression pattern of LPA receptors during mouse brain development by using qRT‐PCR, in situ hybridization, and immunocytochemistry. Only LPA1, LPA2,LPA4, and LPA6 mRNA transcripts were detected throughout development stages from embryonic day 16 until postnatal day 30 of hippocampus, neocortex, cerebellum, and bulbus olfactorius in our experiments, while expression of LPA3 and LPA5 genes was below detection level. In addition to our qRT‐PCR results, we also analyzed the cellular protein expression of endogenous LPA receptors, with focus on LPA1 and LPA2 within postnatal brain slices and primary neuron differentiation with and without cytoskeleton stabilization and destabilization. Conclusions The expression of LPA receptors changes depends on the developmental stage in mouse brain and in cultured hippocampal primary neurons. Interestingly, we found that commercially available antibodies for LPA receptors are largely unspecific.
LPA1, ‐2, ‐4, and ‐6 genes are dynamically expressed during postnatal brain development. LPA1, ‐2, ‐4, and ‐6 genes are differently expressed in the hippocampus, neocortex, cerebellum, and bulbus olfactorius. LPA1 and ‐2 gene expression alters during neuronal differentiation. LPA1, ‐2, ‐3, ‐4, and ‐6 genes are expressed in glia cells, but differed in gene expression levels.
Collapse
Affiliation(s)
- Olga Suckau
- Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Isabel Gross
- Institute of Anatomy, Universitätsmedizin Rostock, Rostock, Germany.,Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| | - Sandra Schrötter
- Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Fan Yang
- Albrecht Kossel Institute for Neuroregeneration, Rostock University Medical Center, Rostock, Germany
| | - Jiankai Luo
- Albrecht Kossel Institute for Neuroregeneration, Rostock University Medical Center, Rostock, Germany
| | - Andreas Wree
- Institute of Anatomy, Universitätsmedizin Rostock, Rostock, Germany
| | - Jerold Chun
- Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California
| | - David Baska
- Translational Animal Research Center, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Jan Baumgart
- Translational Animal Research Center, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Kuniyuki Kano
- Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo, Japan
| | - Junken Aoki
- Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo, Japan
| | - Anja U Bräuer
- Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Institute of Anatomy, Universitätsmedizin Rostock, Rostock, Germany.,Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.,Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| |
Collapse
|
|
34
|
Yu M, Wang Y, Wang Z, Liu Y, Yu Y, Gao X. Taurine Promotes Milk Synthesis via the GPR87-PI3K-SETD1A Signaling in BMECs. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:1927-1936. [PMID: 30678459 DOI: 10.1021/acs.jafc.8b06532] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Taurine, a β-aminosulfonic acid, exerts many cellular physiological functions. It is still unknown whether taurine can regulate milk synthesis in the mammary gland. Therefore, in this study we investigated the effects and mechanism of taurine on milk synthesis in mammary epithelial cells (MECs). Bovine MECs (BMECs) cultured in FBS-free OPTI-MEMImedium were treated with taurine (0, 0.08, 0.16, 0.24, 0.32, and 0.4 mM). Taurine treatment led to increased milk protein and fat synthesis, mTOR phosphorylation, and SREBP-1c protein expression, in a dose-dependent manner, with an apparent maximum at 0.24 mM. Gene function study approaches revealed that the GPR87-PI3K-SETD1A signaling was required for taurine to increase the mTOR and SREBP-1c mRNA levels. Taurine stimulated GPR87 expression and cell membrane localization in a dose dependent manner, suggesting a sensing mechanism of GPR87 to extracellular taurine. Collectively, these data demonstrate that taurine promotes milk synthesis via the GPR87-PI3K-SETD1A signaling.
Collapse
Affiliation(s)
- Mengmeng Yu
- Agricultural College of Guangdong Ocean University , Zhanjiang , 524088 , China
| | - Yang Wang
- The Key Laboratory of Dairy Science of Education Ministry , Northeast Agricultural University , Harbin , 150030 , China
| | - Zhe Wang
- The Key Laboratory of Dairy Science of Education Ministry , Northeast Agricultural University , Harbin , 150030 , China
| | - Yanxu Liu
- The Key Laboratory of Dairy Science of Education Ministry , Northeast Agricultural University , Harbin , 150030 , China
| | - Yang Yu
- The Key Laboratory of Dairy Science of Education Ministry , Northeast Agricultural University , Harbin , 150030 , China
| | - Xuejun Gao
- Agricultural College of Guangdong Ocean University , Zhanjiang , 524088 , China
| |
Collapse
|
|
35
|
Yang F, Chen GX. Production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis. World J Gastroenterol 2018; 24:4132-4151. [PMID: 30271079 PMCID: PMC6158478 DOI: 10.3748/wjg.v24.i36.4132] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 04/24/2018] [Accepted: 05/06/2018] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in sub-millimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin (ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.
Collapse
Affiliation(s)
- Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, United States
| |
Collapse
|
|
36
|
Lidgerwood GE, Pitson SM, Bonder C, Pébay A. Roles of lysophosphatidic acid and sphingosine-1-phosphate in stem cell biology. Prog Lipid Res 2018; 72:42-54. [PMID: 30196008 DOI: 10.1016/j.plipres.2018.09.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/15/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023]
Abstract
Stem cells are unique in their ability to self-renew and differentiate into various cell types. Because of these features, stem cells are key to the formation of organisms and play fundamental roles in tissue regeneration and repair. Mechanisms controlling their fate are thus fundamental to the development and homeostasis of tissues and organs. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids that play a wide range of roles in multiple cell types, during developmental and pathophysiological events. Considerable evidence now demonstrates the potent roles of LPA and S1P in the biology of pluripotent and adult stem cells, from maintenance to repair. Here we review their roles for each main category of stem cells and explore how those effects impact development and physiopathology.
Collapse
Affiliation(s)
- Grace E Lidgerwood
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Claudine Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Alice Pébay
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia.
| |
Collapse
|
|
37
|
Ninou I, Magkrioti C, Aidinis V. Autotaxin in Pathophysiology and Pulmonary Fibrosis. Front Med (Lausanne) 2018; 5:180. [PMID: 29951481 PMCID: PMC6008954 DOI: 10.3389/fmed.2018.00180] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/25/2018] [Indexed: 12/17/2022] Open
Abstract
Lysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2), or as more widely known Autotaxin (ATX), a secreted lysophospholipase D (lysoPLD) largely responsible for extracellular lysophosphatidic acid (LPA) production. In turn, LPA is a bioactive phospholipid autacoid, forming locally upon increased ATX levels and acting also locally through its receptors, likely guided by ATX's structural conformation and cell surface associations. Increased ATX activity levels have been detected in many inflammatory and fibroproliferative conditions, while genetic and pharmacologic studies have confirmed a pleiotropic participation of ATX/LPA in different processes and disorders. In pulmonary fibrosis, ATX levels rise in the broncheoalveolar fluid (BALF) and stimulate LPA production. LPA engagement of its receptors activate multiple G-protein mediated signal transduction pathways leading to different responses from pulmonary cells including the production of pro-inflammatory signals from stressed epithelial cells, the modulation of endothelial physiology, the activation of TGF signaling and the stimulation of fibroblast accumulation. Genetic or pharmacologic targeting of the ATX/LPA axis attenuated disease development in animal models, thus providing the proof of principle for therapeutic interventions.
Collapse
Affiliation(s)
- Ioanna Ninou
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Christiana Magkrioti
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Vassilis Aidinis
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| |
Collapse
|
|
38
|
Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival. Signal Transduct Target Ther 2018; 3:11. [PMID: 29682330 PMCID: PMC5908807 DOI: 10.1038/s41392-017-0005-2] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 11/27/2017] [Accepted: 12/13/2017] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is generally a fatal disease with no efficacious treatment modalities. Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed. Here, we review the role of Yes-associated protein (YAP) and WW-domain-containing Transcriptional co-Activator with a PDZ-binding motif (TAZ) in the development of PDAC. These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes. We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database (www.proteinatlas.org/pathology) that allows genome-wide exploration of the impact of individual proteins on survival outcomes. Multiple YAP/TEAD-regulated genes, including AJUBA, ANLN, AREG, ARHGAP29, AURKA, BUB1, CCND1, CDK6, CXCL5, EDN2, DKK1, FOSL1,FOXM1, HBEGF, IGFBP2, JAG1, NOTCH2, RHAMM, RRM2, SERP1, and ZWILCH, are associated with unfavorable survival of PDAC patients. Similarly, components of AP-1 that synergize with YAP (FOSL1), growth factors (TGFα, EPEG, and HBEGF), a specific integrin (ITGA2), heptahelical receptors (P2Y2R, GPR87) and an inhibitor of the Hippo pathway (MUC1), all of which stimulate YAP activity, are associated with unfavorable survival of PDAC patients. By contrast, YAP inhibitory pathways (STRAD/LKB-1/AMPK, PKA/LATS, and TSC/mTORC1) indicate a favorable prognosis. These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients. We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease. Yes-associated protein (YAP) signaling contributes to pancreatic cancer progression and is associated with poor patient survival. Previous studies have shown that YAP activates genes involved in cell proliferation to incite tumor growth and metastasis. Enrique Rozengurt and colleagues at University of California Los Angeles review the latest knowledge on YAP signaling and used the open access database The Human Protein Atlas to analyze the gene expression profile and prognosis of 176 patients with pancreatic ductal adenocarcinoma. Activation of upstream or downstream elements of the YAP signaling pathway correlated with shorter survival in patients. Conversely, the activation of signaling pathways that oppose YAP signaling were associated with a more favorable prognosis. These findings highlight YAP signaling pathway components as both prognostic markers and potential targets for developing much needed therapeutic and preventative strategies.
Collapse
|
|
39
|
Son SH, Baek SI, Ju MS, Han SG, Jung ST, Yu YG. Development of Single-Chain Antibodies Specific to Lysophosphatidic Acid Receptor 2. B KOREAN CHEM SOC 2018. [DOI: 10.1002/bkcs.11414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Sang Hyeon Son
- Department of Applied Chemistry; Kookmin University; Seoul 02707 South Korea
| | - Seung-il Baek
- Department of Applied Chemistry; Kookmin University; Seoul 02707 South Korea
| | - Man-Seok Ju
- Department of Applied Chemistry; Kookmin University; Seoul 02707 South Korea
| | - Seong-Gu Han
- Department of Applied Chemistry; Kookmin University; Seoul 02707 South Korea
| | - Sang Taek Jung
- Department of Applied Chemistry; Kookmin University; Seoul 02707 South Korea
| | - Yeon Gyu Yu
- Department of Applied Chemistry; Kookmin University; Seoul 02707 South Korea
| |
Collapse
|
|
40
|
Benesch MGK, MacIntyre ITK, McMullen TPW, Brindley DN. Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation. Cancers (Basel) 2018; 10:cancers10030073. [PMID: 29543710 PMCID: PMC5876648 DOI: 10.3390/cancers10030073] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/10/2018] [Accepted: 03/12/2018] [Indexed: 12/13/2022] Open
Abstract
A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice.
Collapse
Affiliation(s)
- Matthew G K Benesch
- Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL AlB 3V6, Canada.
- Signal Transduction Research Group, Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
| | - Iain T K MacIntyre
- Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL AlB 3V6, Canada.
| | - Todd P W McMullen
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G7, Canada.
| | - David N Brindley
- Signal Transduction Research Group, Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
| |
Collapse
|
|
41
|
Dario MFR, Sara T, Estela CO, Margarita PM, Guillermo ET, Fernando RDF, Javier SL, Carmen P. Stress, Depression, Resilience and Ageing: A Role for the LPA-LPA1 Pathway. Curr Neuropharmacol 2018; 16:271-283. [PMID: 28699486 PMCID: PMC5843979 DOI: 10.2174/1570159x15666170710200352] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 05/26/2017] [Accepted: 06/30/2017] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Chronic stress affects health and the quality of life, with its effects being particularly relevant in ageing due to the psychobiological characteristics of this population. However, while some people develop psychiatric disorders, especially depression, others seem very capable of dealing with adversity. There is no doubt that along with the identification of neurobiological mechanisms involved in developing depression, discovering which factors are involved in positive adaptation under circumstances of extreme difficulty will be crucial for promoting resilience. METHODS Here, we review recent work in our laboratory, using an animal model lacking the LPA1 receptor, together with pharmacological studies and clinical evidence for the possible participation of the LPA1 receptor in mood and resilience to stress. RESULTS Substantial evidence has shown that the LPA1 receptor is involved in emotional regulation and in coping responses to chronic stress, which, if dysfunctional, may induce vulnerability to stress and predisposition to the development of depression. Given that there is commonality of mechanisms between those involved in negative consequences of stress and in ageing, this is not surprising, considering that the LPA1 receptor may be involved in coping with adversity during ageing. CONCLUSION Alterations in this receptor may be a susceptibility factor for the presence of depression and cognitive deficits in the elderly population. However, because this is only a promising hypothesis based on previous data, future studies should focus on the involvement of the LPA-LPA1 pathway in coping with stress and resilience in ageing.
Collapse
Affiliation(s)
- Moreno-Fernández Román Dario
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
| | - Tabbai Sara
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
| | - Castilla-Ortega Estela
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga; Málaga 29010, Spain
| | - Pérez-Martín Margarita
- Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de
Málaga; Málaga 29071, Spain
| | - Estivill-Torrús Guillermo
- Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitarios de Málaga, Málaga, Spain
| | - Rodríguez de Fonseca Fernando
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga; Málaga 29010, Spain
| | - Santin Luis Javier
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
| | - Pedraza Carmen
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
| |
Collapse
|
|
42
|
Zhang X, Biagini Myers JM, Yadagiri VK, Ulm A, Chen X, Weirauch MT, Khurana Hershey GK, Ji H. Nasal DNA methylation differentiates corticosteroid treatment response in pediatric asthma: A pilot study. PLoS One 2017; 12:e0186150. [PMID: 29028809 PMCID: PMC5640236 DOI: 10.1371/journal.pone.0186150] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/26/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Treatment response to systemic corticosteroid in asthmatic children is heterogeneous and may be mediated by epigenetic mechanism(s). We aim to identify DNA methylation (DNAm) changes responsive to steroid, and DNAm biomarkers that distinguish treatment response. MATERIALS AND METHODS We followed 33 children (ages 5-18) presenting to the Emergency Department (ED) for asthma exacerbation. Based on whether they met discharge criteria in ≤24 hours, participants were grouped into good and poor responders to steroid treatment. Nasal samples were collected upon presentation to the ED (T0) and 18-24 hours later (T1). Genome-wide DNAm was measured for both time points in 20 subjects, and compared between T0 and T1 in good and poor responders respectively. DNAm at T1 was also compared between two responder groups. DNAm of selected CpGs was verified in the complete cohort, and expression of associated genes was examined. Interactions between DNAm, common single nucleotide polymorphism (SNP) located at the CpG sites and treatment responses were assessed. RESULTS Three CpGs located in the OTX2 promoter showed responder-specific DNAm changes from T0 to T1, in which DNAm decreased in good but not in poor responders. Good and poor responders showed differential DNAm at T1 in 127 CpGs without and 182 CpGs with common SNP co-localization. Negative correlations between DNAm and gene expression were observed at CpGs located within the LDHC promoter, suggesting an impact of DNAm on gene regulation. Interactions between SNPs, DNAm and treatment response were detected. CONCLUSION Acute systemic steroid treatment modifies nasal DNAm in good responders. Nasal DNAm, dependent or independent of SNPs, can differentiate response to treatment in acute asthmatic children.
Collapse
Affiliation(s)
- Xue Zhang
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Jocelyn M. Biagini Myers
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Veda K. Yadagiri
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Ashley Ulm
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Xiaoting Chen
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Matthew T. Weirauch
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Gurjit K. Khurana Hershey
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Hong Ji
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
- * E-mail:
| |
Collapse
|
|
43
|
Le Duc D, Schulz A, Lede V, Schulze A, Thor D, Brüser A, Schöneberg T. P2Y Receptors in Immune Response and Inflammation. Adv Immunol 2017; 136:85-121. [PMID: 28950952 DOI: 10.1016/bs.ai.2017.05.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Metabotropic pyrimidine and purine nucleotide receptors (P2Y receptors) are expressed in virtually all cells with implications in very diverse biological functions, including the well-established platelet aggregation (P2Y12), but also immune regulation and inflammation. The classical P2Y receptors bind nucleotides and are encoded by eight genes with limited sequence homology, while phylogenetically related receptors (e.g., P2Y12-like) recognize lipids and peptides, but also nucleotide derivatives. Growing lines of evidence suggest an important function of P2Y receptors in immune cell differentiation and maturation, migration, and cell apoptosis. Here, we give a perspective on the P2Y receptors' molecular structure and physiological importance in immune cells, as well as the related diseases and P2Y-targeting therapies. Extensive research is being undertaken to find modulators of P2Y receptors and uncover their physiological roles. We anticipate the medical applications of P2Y modulators and their immune relevance.
Collapse
Affiliation(s)
- Diana Le Duc
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany
| | - Angela Schulz
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany
| | - Vera Lede
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany
| | - Annelie Schulze
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany
| | - Doreen Thor
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany
| | - Antje Brüser
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany
| | | |
Collapse
|
|
44
|
Lopane C, Agosti P, Gigante I, Sabbà C, Mazzocca A. Implications of the lysophosphatidic acid signaling axis in liver cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:277-282. [PMID: 28591560 DOI: 10.1016/j.bbcan.2017.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 05/30/2017] [Accepted: 06/01/2017] [Indexed: 01/25/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in western countries. The major risk factors for HCC are hepatitis C or B viruses, alcohol and metabolic disorders. The increasing risk of HCC in patients with metabolic disorders (i.e. obesity, diabetes and non-alcoholic steatohepatitis/NASH) regardless of the presence of liver cirrhosis is becoming relevant. Nevertheless, molecular mechanisms linking these risk factors to liver oncogenesis are unclear. This review focuses on the pathogenic role of the lysophosphatidic acid (LPA) pathway in HCC, highlighting the implications of this bioactive phospholipid in liver cancer biology and metabolism and as potential therapeutic target.
Collapse
Affiliation(s)
- Chiara Lopane
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Pasquale Agosti
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Isabella Gigante
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy.
| |
Collapse
|
|
45
|
Quan M, Cui JJ, Feng X, Huang Q. The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer. Tumour Biol 2017; 39:1010428317694544. [PMID: 28347252 DOI: 10.1177/1010428317694544] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.
Collapse
Affiliation(s)
- Ming Quan
- Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Jiu-Jie Cui
- Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Xiao Feng
- Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Qian Huang
- Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| |
Collapse
|
|
46
|
Han SG, Baek SI, Son TJ, Lee H, Kim NH, Yu YG. Preparation of functional human lysophosphatidic acid receptor 2 using a P9 ∗ expression system and an amphipathic polymer and investigation of its in vitro binding preference to G α proteins. Biochem Biophys Res Commun 2017; 487:103-108. [PMID: 28392399 DOI: 10.1016/j.bbrc.2017.04.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 04/06/2017] [Indexed: 12/12/2022]
Abstract
Human lysophosphatidic acid receptor 2 (LPA2), a member of the G-protein coupled receptor family, mediates lysophosphatidic acid (LPA)-dependent signaling by recruiting various G proteins. Particularly, it is directly implicated in the progression of colorectal and ovarian cancer through G protein signaling cascades. To investigate the biochemical binding properties of LPA2 against various alpha subunits of G protein (Gα), a functional recombinant LPA2 was overexpressed in E. coli membrane with a P9∗ expression system, and the purified protein was stabilized with an amphipathic polymer that had been synthesized by coupling octylamine, glucosamine, and diethyl aminoproylamine at the carboxylic groups of poly-γ-glutamic acid. The purified LPA2 stabilized with the amphipathic polymer showed selective binding activity to the various Gα proteins as well as agonist-dependent dissociation from Gαi3. Understanding the binding properties of LPA2 against various Gα proteins advances the understanding of downstream signaling cascades of LPA2. The functional LPA2 prepared using a P9∗ expression system and an amphipathic polymer could also facilitate the development of LPA2-targeting drugs.
Collapse
Affiliation(s)
- Seong-Gu Han
- Department of Chemistry, Kookmin University, 861-1 Jeongneung-dong, Seongbuk-gu, Seoul 136-702, South Korea
| | - Seung-Il Baek
- Department of Chemistry, Kookmin University, 861-1 Jeongneung-dong, Seongbuk-gu, Seoul 136-702, South Korea
| | - Tae Jin Son
- Department of Chemistry, Kookmin University, 861-1 Jeongneung-dong, Seongbuk-gu, Seoul 136-702, South Korea
| | - Hyeongjin Lee
- Department of Chemistry, Kookmin University, 861-1 Jeongneung-dong, Seongbuk-gu, Seoul 136-702, South Korea
| | - Nam Hyuk Kim
- Department of Chemistry, Kookmin University, 861-1 Jeongneung-dong, Seongbuk-gu, Seoul 136-702, South Korea
| | - Yeon Gyu Yu
- Department of Chemistry, Kookmin University, 861-1 Jeongneung-dong, Seongbuk-gu, Seoul 136-702, South Korea.
| |
Collapse
|
|
47
|
Wang L, Zhou W, Zhong Y, Huo Y, Fan P, Zhan S, Xiao J, Jin X, Gou S, Yin T, Wu H, Liu T. Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway. Mol Cancer 2017; 16:61. [PMID: 28288630 PMCID: PMC5348802 DOI: 10.1186/s12943-017-0627-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 02/27/2017] [Indexed: 12/13/2022] Open
Abstract
Background Pancreatic cancer is a highly lethal disease and has the worst prognosis of any major malignancy. G protein-coupled receptor GPR87 is reported to be overexpressed in multiple cancers. The clinical significance and biological role of GPR87 in pancreatic cancer, however, remain to be established. Methods GPR87 expression in pancreatic cancer cell lines, paired patient tissues were determined using western blotting and Real-time PCR. Ninety-six human pancreatic cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the association between GPR87 expression and the clinicopathological characteristics of pancreatic cancer. Functional assays, such as anchorage-independent growth, chicken chorioallantoic membrane (CAM) assay, transwell matrix penetration assay, and Annexin V-FITC and PI staining and a xenograft tumor model were used to determine the oncogenic role of GPR87 in human pancreatic cancer progression. The effect of GPR87 on NF-κB signaling pathway was further investigated using the luciferase reporter assays, and by detection of the NF-κB signaling downstream genes. Results Herein, we reported that GPR87 was markedly overexpressed in pancreatic cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of GPR87 significantly correlated with patients’ clinicopathologic features, including clinical stage and tumor-nodule-metastasis (TNM) classification. Pancreatic cancer patients with higher levels of GPR87 expression had shorter overall survival compared to patients with lower GPR87 levels. We gained valuable insights into the mechanism of GPR87 expression in pancreatic cancer cells by demonstrating that overexpressing GPR87 significantly enhanced, whereas silencing endogenous GPR87 inhibited, the proliferation, angiogenesis and increased resistance to gemcitabine-induced apoptosis of pancreatic cancer in vitro and tumorigenicity of pancreatic cancer cells in vivo. Finally, we demonstrated that GPR87 enhanced pancreatic cancer aggressiveness by activating NF-κB signaling pathway. Conclusions: Taken together, these findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy. Conclusions Our findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0627-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Li Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China
| | - Wei Zhou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Yunfeng Zhong
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Yongbao Huo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Ping Fan
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Sudong Zhan
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Jun Xiao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Xin Jin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Shanmiao Gou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Tao Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Tao Liu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China. .,Department of Digestive Surgical Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
| |
Collapse
|
|
48
|
Han SG, Baek SI, Lee WK, Sudakar P, Yu YG. Overexpression and Functional Stabilization of Recombinant Human Lysophosphatidic Acid Receptor 1 Using an Amphiphatic Polymer. B KOREAN CHEM SOC 2017. [DOI: 10.1002/bkcs.11048] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Seong-Gu Han
- Department of Chemistry; Kookmin University; Seoul 136-702 Korea
| | - Seung-Il Baek
- Department of Chemistry; Kookmin University; Seoul 136-702 Korea
| | - Won-Kyu Lee
- Department of Chemistry; Kookmin University; Seoul 136-702 Korea
- New Drug Development Center; Osong Medical Innovation Foundation; Cheongju-si 28160 Korea
| | | | - Yeon Gyu Yu
- Department of Chemistry; Kookmin University; Seoul 136-702 Korea
| |
Collapse
|
|
49
|
Niss Arfelt K, Fares S, Sparre-Ulrich AH, Hjortø GM, Gasbjerg LS, Mølleskov-Jensen AS, Benned-Jensen T, Rosenkilde MM. Signaling via G proteins mediates tumorigenic effects of GPR87. Cell Signal 2016; 30:9-18. [PMID: 27865873 DOI: 10.1016/j.cellsig.2016.11.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 11/12/2016] [Accepted: 11/12/2016] [Indexed: 12/16/2022]
Abstract
G protein-coupled receptors (GPCRs) constitute a large protein family of seven transmembrane (7TM) spanning proteins that regulate multiple physiological functions. GPR87 is overexpressed in several cancers and plays a role in tumor cell survival. Here, the basal activity of GPR87 was investigated in transiently transfected HEK293 cells, revealing ligand-independent coupling to Gαi, Gαq and Gα12/13. Furthermore, GPR87 showed a ligand-independent G protein-dependent activation of the downstream transcription factors CREB, NFκB, NFAT and SRE. In tetracycline-induced Flp-In T-Rex-293 cells, GPR87 induced cell clustering presumably through Gα12/13 coupling. In a foci formation assay using retrovirally transduced NIH3T3 cells, GPR87 showed a strong in vitro transforming potential, which correlated to the in vivo tumor induction in nude mice. Importantly, we demonstrate that the transforming potential of GPR87 was correlated to the receptor signaling, as the signaling-impaired mutant R139A (Arg in the conserved "DRY"-motif at the bottom of transmembrane helix 3 of GPR87 substituted to Ala) showed a lower in vitro cell transformation potential. Furthermore, R139A lost the ability to induce cell clustering. In summary, we show that GPR87 is active through several signaling pathways and that the signaling activity is linked to the receptor-induced cell transformation and clustering. The robust surface expression of GPR87 and general high druggability of GPCRs make GPR87 an attractive future anticancer target for drugs that - through inhibition of the receptor signaling - will inhibit its transforming properties.
Collapse
Affiliation(s)
- Kristine Niss Arfelt
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Suzan Fares
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alexander H Sparre-Ulrich
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Gertrud M Hjortø
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lærke S Gasbjerg
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ann-Sofie Mølleskov-Jensen
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tau Benned-Jensen
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
50
|
Histone variant H3F3A promotes lung cancer cell migration through intronic regulation. Nat Commun 2016; 7:12914. [PMID: 27694942 PMCID: PMC5477500 DOI: 10.1038/ncomms12914] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 08/16/2016] [Indexed: 01/12/2023] Open
Abstract
Although several somatic single nucleotide variations in histone H3.3 have been investigated as cancer drivers, other types of aberration have not been well studied. Here, we demonstrate that overexpression of H3F3A, encoding H3.3, is associated with lung cancer progression and promotes lung cancer cell migration by activating metastasis-related genes. H3.3 globally activates gene expression through the occupation of intronic regions in lung cancer cells. Moreover, H3.3 binding regions show characteristics of regulatory DNA elements. We show that H3.3 is deposited at a specific intronic region of GPR87, where it modifies the chromatin status and directly activates GPR87 transcription. The expression levels of H3F3A and GPR87, either alone or in combination, are robust prognostic markers for early-stage lung cancer, and may indicate potential for the development of treatments involving GPR87 antagonists. In summary, our results demonstrate that intronic regulation by H3F3A may be a target for the development of novel therapeutic strategies. Histone variants act as transcriptional activators and repressors and have been linked to cancer progression. Park and Choi et al. show that the histone H3.3 overexpression is associated with early-stage lung cancer, and promotes cancer cell migration by upregulating a G-protein-coupled receptor.
Collapse
|