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Mousavikia SN, Matin MM, Bahreyni Tossi MT, Azimian H. Unraveling the role of the P2X7 receptor in cancer radioresistance: Molecular insights and therapeutic implications. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119910. [PMID: 39889832 DOI: 10.1016/j.bbamcr.2025.119910] [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: 10/10/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/03/2025]
Abstract
The P2X7 receptor, a key player in purinergic signaling, is a crucial factor in modulating the response of cancer cells to radiotherapy. The aim of this study was to elucidate the molecular mechanisms by which P2X7 receptor activation contributes to radioresistance in different cancer types. P2X7 receptor signaling influences cellular processes such as DNA damage repair and inflammatory responses, thereby improving tumor survival after radiation exposure. Activation of the P2X7 receptor leads to changes in the tumor microenvironment and promotes an adaptive response that enables cancer cells to resist therapeutic interventions. Therefore, targeting the P2X7 receptor could represent a new therapeutic strategy against cancer. By linking molecular insights with therapeutic implications, this research highlights the P2X7 receptor as a promising target for overcoming radioresistance in cancer therapy and paves the way for novel combination approaches that could significantly improve patient outcomes.
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Affiliation(s)
- Seyedeh Nasibeh Mousavikia
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mohammad Taghi Bahreyni Tossi
- Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hosein Azimian
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Physics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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da Silva ÁC, Scholl JN, de Fraga Dias A, Weber AF, Morrone FB, Cruz-López O, Conejo-García A, Campos JM, Sévigny J, Figueiró F, Battastini AMO. Preclinical evaluation of bozepinib in bladder cancer cell lines: modulation of the NPP1 enzyme. Purinergic Signal 2025; 21:39-50. [PMID: 37906424 PMCID: PMC11958895 DOI: 10.1007/s11302-023-09975-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 10/20/2023] [Indexed: 11/02/2023] Open
Abstract
Bladder cancer (BC) is the most common cancer of the urinary tract. Bozepinib (BZP), a purine-derived molecule, is a potential compound for the treatment of cancer. Purinergic signaling consists of the activity of nucleosides and nucleotides present in the extracellular environment, modulating a variety of biological actions. In cancer, this signaling is mainly controlled by the enzymatic cascade involving the NTPDase/E-NPP family and ecto-5'-nucleotidase/CD73, which hydrolyze extracellular adenosine triphosphate (ATP) to adenosine (ADO). The aim of this work is to evaluate the activity of BZP in the purinergic system in BC cell lines and to compare its in vitro antitumor activity with cisplatin, a chemotherapeutic drug widely used in the treatment of BC. In this study, two different BC cell lines, grade 1 RT4 and the more aggressive grade 3 T24, were used along with a human fibroblast cell line MRC-5, a cell used to predict the selectivity index (SI). BZP shows strong antitumor activity, with notable IC50 values (8.7 ± 0.9 µM for RT4; 6.7 ± 0.7 µM for T24), far from the SI for cisplatin (SI for BZP: 19.7 and 25.7 for RT4 and T24, respectively; SI for cisplatin: 1.7 for T24). BZP arrests T24 cells in the G2/M phase of the cell cycle, inducing early apoptosis. Moreover, BZP increases ATP and ADP hydrolysis and gene/protein expression of the NPP1 enzyme in the T24 cell line. In conclusion, BZP shows superior activity compared to cisplatin against BC cell lines in vitro.
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Affiliation(s)
- Álisson Coldebella da Silva
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Juliete Nathali Scholl
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Amanda de Fraga Dias
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Augusto Ferreira Weber
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
| | - Fernanda Bueno Morrone
- Laboratório de Farmacologia Aplicada, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Olga Cruz-López
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Ana Conejo-García
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Joaquín María Campos
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Jean Sévigny
- Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada
- Axe maladies infectieuses et immunitaires, Centre de recherche du CHU de Québec - Université Laval, Quebec city, QC, Canada
| | - Fabrício Figueiró
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ana Maria Oliveira Battastini
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - anexo, Porto Alegre, CEP 90035-003, RS, Brazil.
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Tang X, Wang H, Liu H, Li G, Sturgis EM, Shete S, Wei Q. Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma. Mol Carcinog 2024; 63:1712-1721. [PMID: 38860607 PMCID: PMC11329348 DOI: 10.1002/mc.23767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 05/08/2024] [Accepted: 05/20/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC). METHODS We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants. RESULTS There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels. CONCLUSIONS Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.
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Affiliation(s)
- Xiaozhun Tang
- Department of Head and Neck Surgery, the Affiliated Cancer Hospital of Guangxi Medical University, Guangxi Cancer Hospital, Nanning, China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Huiling Wang
- Department of Head and Neck Surgery, the Affiliated Cancer Hospital of Guangxi Medical University, Guangxi Cancer Hospital, Nanning, China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Erich M. Sturgis
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Sanjay Shete
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
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Fierro-Arenas A, Landskron G, Camhi-Vainroj I, Basterrechea B, Parada-Venegas D, Lobos-González L, Dubois-Camacho K, Araneda C, Romero C, Domínguez A, Vásquez G, López-K F, Alvarez K, González CM, Hager Ribeiro C, Balboa E, Eugenin E, Hermoso MA, De la Fuente López M. Pannexin-1 expression in tumor cells correlates with colon cancer progression and survival. Life Sci 2024; 351:122851. [PMID: 38897345 DOI: 10.1016/j.lfs.2024.122851] [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: 02/05/2024] [Revised: 06/11/2024] [Accepted: 06/14/2024] [Indexed: 06/21/2024]
Abstract
AIMS Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in colon cancer remains poorly understood, thus constituting the focus of this study. MAIN METHODS PANX1 mRNA expression was analyzed using multiple cancer databases. PANX1 protein expression and distribution were evaluated by immunohistochemistry on primary tumor tissue and non-tumor colonic mucosa from colon cancer patients. PANX1 inhibitors (probenecid or 10Panx) were used to assess colon cancer cell lines viability. To study the role of PANX1 in vivo, a subcutaneous xenograft model using HCT116 cells was performed in BALB/c NOD/SCID immunodeficient mice to evaluate tumor growth under PANX1 inhibition using probenecid. KEY FINDINGS PANX1 mRNA was upregulated in colon cancer tissue compared to non-tumor colonic mucosa. Elevated PANX1 mRNA expression in tumors correlated with worse disease-free survival. PANX1 protein abundance was increased on tumor cells compared to epithelial cells in paired samples, in a cancer stage-dependent manner. In vitro and in vivo experiments indicated that blocking PANX1 reduced cell viability and tumor growth. SIGNIFICANCE PANX1 can be used as a biomarker of colon cancer progression and blocking PANX1 channel opening could be used as a potential therapeutic strategy against this disease.
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Affiliation(s)
- Aaron Fierro-Arenas
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile; Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Glauben Landskron
- Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clínica Las Condes, Universidad Finis Terrae, Santiago, Chile
| | - Ilan Camhi-Vainroj
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Benjamín Basterrechea
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Daniela Parada-Venegas
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile; Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lorena Lobos-González
- Regenerative Medicine Center, Faculty of Medicine, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Karen Dubois-Camacho
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile; Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Catalina Araneda
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile; Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clínica Las Condes, Universidad Finis Terrae, Santiago, Chile
| | - Camila Romero
- Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clínica Las Condes, Universidad Finis Terrae, Santiago, Chile
| | - Antonia Domínguez
- Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clínica Las Condes, Universidad Finis Terrae, Santiago, Chile
| | - Gonzalo Vásquez
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile; Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clínica Las Condes, Universidad Finis Terrae, Santiago, Chile
| | | | - Karin Alvarez
- Cancer Center, Clínica Universidad de los Andes, Santiago, Chile
| | - Carlos M González
- School of Veterinary Medicine, Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile
| | | | - Elisa Balboa
- Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clínica Las Condes, Universidad Finis Terrae, Santiago, Chile
| | - Eliseo Eugenin
- Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch (UTMB), Galveston, USA
| | - Marcela A Hermoso
- Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Universidad de Chile, Santiago, Chile; Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marjorie De la Fuente López
- Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clínica Las Condes, Universidad Finis Terrae, Santiago, Chile.
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Li R, Lei Y, Rezk A, Diego A Espinoza, Wang J, Feng H, Zhang B, Barcelos IP, Zhang H, Yu J, Huo X, Zhu F, Yang C, Tang H, Goldstein AC, Banwell BL, Hakonarson H, Xu H, Mingueneau M, Sun B, Li H, Bar-Or A. Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis. Sci Immunol 2024; 9:eadk0865. [PMID: 38701189 DOI: 10.1126/sciimmunol.adk0865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 04/10/2024] [Indexed: 05/05/2024]
Abstract
Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.
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Affiliation(s)
- Rui Li
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute of Immunotherapy and Department of Neurology of First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Yanting Lei
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Ayman Rezk
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Diego A Espinoza
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jing Wang
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Huiru Feng
- Institute of Immunotherapy and Department of Neurology of First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Bo Zhang
- Institute of Immunotherapy and Department of Neurology of First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Isabella P Barcelos
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hang Zhang
- Department of Immunology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jing Yu
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Xinrui Huo
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Fangyi Zhu
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Changxin Yang
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Hao Tang
- MS Research Unit, Biogen, Cambridge, MA 02142, USA
| | - Amy C Goldstein
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Brenda L Banwell
- Division of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Hongwei Xu
- Department of Immunology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | | | - Bo Sun
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Hulun Li
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Amit Bar-Or
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- MS Research Unit, Biogen, Cambridge, MA 02142, USA
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Zhang H, Song J, Ward R, Han Y, Hunt A, Shriwas P, Steed A, Edwards C, Cao Y, Co M, Chen X. Diverse temporal and spatial mechanisms work, partially through Stanniocalcin-1, V-ATPase and senescence, to activate the extracellular ATP-mediated drug resistance in human cancer cells. Front Oncol 2024; 14:1276092. [PMID: 38380370 PMCID: PMC10876858 DOI: 10.3389/fonc.2024.1276092] [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: 08/11/2023] [Accepted: 01/17/2024] [Indexed: 02/22/2024] Open
Abstract
Introduction Resistance to drug therapies is associated with a large majority of cancer-related deaths. ATP-binding cassette (ABC) transporter-mediated drug efflux, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), glutathione (GSH), senescence, and vacuole-type ATPase (V-ATPase) all contribute to the resistance. We recently showed that extracellular ATP (eATP) induces and regulates EMT, CSC formation, and ABC transporters in human cancer cells and tumors. eATP also consistently upregulates Stanniocalcin-1 (STC1), a gene that significantly contributes to EMT, CSC formation, and tumor growth. We also found that eATP enhances drug resistance in cancer cells through eATP internalization mediated by macropinocytosis, leading to an elevation of intracellular ATP (iATP) levels, induction of EMT, and CSC formation. However, these factors have never been systematically investigated in the context of eATP-induced drug resistance. Methods In this study, we hypothesized that eATP increases drug resistance via inducing ABC efflux, EMT, CSCs, STC1, and their accompanied processes such as GSH reducing activity, senescence, and V-ATPase. RNA sequencing, metabolomics, gene knockdown and knockout, and functional assays were performed to investigate these pathways and processes. Results and discussion Our study results showed that, in multiple human cancer lines, eATP induced genes involved in drug resistance, elevated ABC transporters' efflux activity of anticancer drugs; generated transcriptomic and metabolic profiles representing a drug resistant state; upregulated activities of GSH, senescence, and V-ATPase to promote drug resistance. Collectively, these newly found players shed light on the mechanisms of eATP-induced as well as STC1- and V-ATPase-mediated drug resistance and offer potential novel targets for combating drug resistance in cancers.
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Affiliation(s)
- Haiyun Zhang
- Department of Biological Science, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
- The Program of Molecular and Cellular Biology, Ohio University, Athens, OH, United States
| | - Jingwen Song
- Department of Biological Science, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
- The Program of Molecular and Cellular Biology, Ohio University, Athens, OH, United States
| | - Ryan Ward
- The Honor Tutorial College, Ohio University, Athens, OH, United States
| | - Yong Han
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
| | - Arabella Hunt
- The Honor Tutorial College, Ohio University, Athens, OH, United States
| | - Pratik Shriwas
- Department of Biological Science, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
- The Program of Molecular and Cellular Biology, Ohio University, Athens, OH, United States
| | - Alexander Steed
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Cory Edwards
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Yanyang Cao
- Department of Biological Science, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
- The Program of Molecular and Cellular Biology, Ohio University, Athens, OH, United States
| | - Milo Co
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Xiaozhuo Chen
- Department of Biological Science, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
- The Program of Molecular and Cellular Biology, Ohio University, Athens, OH, United States
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
- Department of Biomedical Science, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
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Azzari NA, Segars KL, Rapaka S, Kushimi L, Rich CB, Trinkaus-Randall V. Aberrations in Cell Signaling Quantified in Diabetic Murine Globes after Injury. Cells 2023; 13:26. [PMID: 38201230 PMCID: PMC10778404 DOI: 10.3390/cells13010026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/12/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
The corneal epithelium is an avascular structure that has a unique wound healing mechanism, which allows for rapid wound closure without compromising vision. This wound healing mechanism is attenuated in diabetic patients, resulting in poor clinical outcomes and recurrent non-healing erosion. We investigated changes in cellular calcium signaling activity during the wound response in murine diabetic tissue using live cell imaging from both ex vivo and in vitro models. The calcium signaling propagation in diabetic cells was significantly decreased and displayed altered patterns compared to non-diabetic controls. Diabetic cells and tissue display distinct expression of the purinergic receptor, P2X7, which mediates the wound healing response. We speculate that alterations in P2X7 expression, interactions with other proteins, and calcium signaling activity significantly impact the wound healing response. This may explain aberrations in the diabetic wound response.
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Affiliation(s)
- Nicholas A. Azzari
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA; (N.A.A.); (C.B.R.)
| | - Kristen L. Segars
- Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA;
| | - Srikar Rapaka
- Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA;
| | - Landon Kushimi
- Department of Computer Science, Center for Computing and Data Sciences, Boston University, 665 Commonwealth Ave, Boston, MA 02115, USA;
| | - Celeste B. Rich
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA; (N.A.A.); (C.B.R.)
| | - Vickery Trinkaus-Randall
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA; (N.A.A.); (C.B.R.)
- Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA;
- Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
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Bai X, Li Q, Peng X, Li X, Qiao C, Tang Y, Zhao R. P2X7 receptor promotes migration and invasion of non-small cell lung cancer A549 cells through the PI3K/Akt pathways. Purinergic Signal 2023; 19:685-697. [PMID: 36854856 PMCID: PMC10754800 DOI: 10.1007/s11302-023-09928-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
It has been demonstrated that the ATP-gated ion channel P2X7 receptor is involved in tumor progression and plays an important role in regulating tumor cell growth, invasion, migration and angiogenesis. However, P2X7 receptors have been relatively poorly studied in non-small cell lung cancer (NSCLC) cells. Therefore, the aim of this study was to investigate the effects of P2X7 receptor on A549 cells (NSCLC cell line) migration and invasion and to reveal the molecular mechanisms mediated by it. We detected the expression and function of P2X7 receptor in A549 cells. The effects and mechanisms of P2X7 receptor on A549 cells migration, invasion, and epithelial-mesenchymal transition were detected in vitro and in vivo. The results showed P2X7 receptor expressed by A549 cells had ion channel and macropore formation function. In addition, activation of P2X7 receptor by adenosine triphosphate (ATP) or 2'(3')-O-(4-Benzoylbenzoyl)-adenosine-5'-triphosphate (BzATP) promoted Epithelial-mesenchymal transition (EMT), migration and invasion of A549 cells, which was attenuated by treatment of cells with P2X7 receptor antagonist A438079 and Oxidized ATP. Furthermore, activation of P2X7 receptor increased phosphorylated protein kinase B (p-Akt) levels, and the phosphatidylinositol-tris-phosphate kinase 3 (PI3K)/protein kinase B (Akt) inhibitor LY294002 blocked migration and invasion of A549 cells induced by ATP or BzATP. At the same time, in vivo results showed that P2X7 receptor could also promote EMT and PI3K/Akt expression in transplanted tumors. Our study indicated that P2X7 receptor promotes A549 cells migration and invasion through the PI3K/Akt signaling pathway, suggesting that P2X7 receptor may be a potential therapeutic target for NSCLC.
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Affiliation(s)
- Xue Bai
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
- Institutional Key Laboratory of Clinical Laboratory Diagnostics, 12Th 5-Year Project of Shandong Province, Weifang Medical University, Weifang, Shandong, China
| | - Qianqian Li
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
- Institutional Key Laboratory of Clinical Laboratory Diagnostics, 12Th 5-Year Project of Shandong Province, Weifang Medical University, Weifang, Shandong, China
- Department of Laboratory Medicine, Qingdao Eighth People's Hospital, Qingdao, Shandong, China
| | - Xiaoxiang Peng
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
- Institutional Key Laboratory of Clinical Laboratory Diagnostics, 12Th 5-Year Project of Shandong Province, Weifang Medical University, Weifang, Shandong, China
| | - Xinyu Li
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
- Institutional Key Laboratory of Clinical Laboratory Diagnostics, 12Th 5-Year Project of Shandong Province, Weifang Medical University, Weifang, Shandong, China
| | - Cuicui Qiao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
- Institutional Key Laboratory of Clinical Laboratory Diagnostics, 12Th 5-Year Project of Shandong Province, Weifang Medical University, Weifang, Shandong, China
| | - Yiqing Tang
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
- Institutional Key Laboratory of Clinical Laboratory Diagnostics, 12Th 5-Year Project of Shandong Province, Weifang Medical University, Weifang, Shandong, China
| | - Ronglan Zhao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China.
- Institutional Key Laboratory of Clinical Laboratory Diagnostics, 12Th 5-Year Project of Shandong Province, Weifang Medical University, Weifang, Shandong, China.
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9
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Huo A, Xiong X. PAICS as a potential target for cancer therapy linking purine biosynthesis to cancer progression. Life Sci 2023; 331:122070. [PMID: 37673296 DOI: 10.1016/j.lfs.2023.122070] [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: 07/04/2023] [Revised: 09/02/2023] [Accepted: 09/02/2023] [Indexed: 09/08/2023]
Abstract
Tumor cells are required to undergo metabolic reprogramming for rapid development and progression, and one of the metabolic characteristics of cancer cells is the excessive synthesis and utilization of nucleotides. Abnormally increased nucleotides and their metabolites not only directly accelerate tumor cell progression but also indirectly act on stromal cells in the tumor microenvironment (TME) via a paracrine manner to regulate tumor progression. Purine nucleotides are mainly produced via de novo nucleotide synthesis in tumor cells; therefore, intervening in their synthesis has emerged as a promising strategy in anti-tumor therapy. De novo purine synthesis is a 10-step reaction catalyzed by six enzymes to synthesize inosine 5-monophosphate (IMP) and subsequently synthesize AMP and GMP. Phosphoribosylaminoimidazole carboxylase/phosphori-bosylaminoimidazole succinocarboxamide synthetase (PAICS) is a bifunctional enzyme that catalyzes de novo purine synthesis. Aberrantly elevated PAICS expression in various tumors is associated with poor prognosis. Evidence suggests that PAICS and its catalytic product, N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR), could inhibit tumor cell apoptosis and promote the growth, epithelial-mesenchymal transition (EMT), invasion, and metastasis by regulating signaling pathways such as pyruvate kinase M2 (PKM2), extracellular signal-related kinases 1 and 2 (ERK1/2), focal adhesion kinase (FAK) and so on. This review summarizes the structure, biological functions and the molecular mechanisms of PAICS in cancer development and discusses its potential to be a target for tumor therapy.
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Affiliation(s)
- Anqi Huo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330006, China; The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi 330031, China
| | - Xiangyang Xiong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330006, China; Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, Jiangxi 330006, China.
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10
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Ai Y, Wang H, Liu L, Qi Y, Tang S, Tang J, Chen N. Purine and purinergic receptors in health and disease. MedComm (Beijing) 2023; 4:e359. [PMID: 37692109 PMCID: PMC10484181 DOI: 10.1002/mco2.359] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 09/12/2023] Open
Abstract
Purines and purinergic receptors are widely distributed throughout the human body. Purine molecules within cells play crucial roles in regulating energy metabolism and other cellular processes, while extracellular purines transmit signals through specific purinergic receptors. The ubiquitous purinergic signaling maintains normal neural excitability, digestion and absorption, respiratory movement, and other complex physiological activities, and participates in cell proliferation, differentiation, migration, and death. Pathological dysregulation of purinergic signaling can result in the development of various diseases, including neurodegeneration, inflammatory reactions, and malignant tumors. The dysregulation or dysfunction of purines and purinergic receptors has been demonstrated to be closely associated with tumor progression. Compared with other subtypes of purinergic receptors, the P2X7 receptor (P2X7R) exhibits distinct characteristics (i.e., a low affinity for ATP, dual functionality upon activation, the mediation of ion channels, and nonselective pores formation) and is considered a promising target for antitumor therapy, particularly in patients with poor response to immunotherapy This review summarizes the physiological and pathological significance of purinergic signaling and purinergic receptors, analyzes their complex relationship with tumors, and proposes potential antitumor immunotherapy strategies from tumor P2X7R inhibition, tumor P2X7R overactivation, and host P2X7R activation. This review provides a reference for clinical immunotherapy and mechanism investigation.
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Affiliation(s)
- Yanling Ai
- Department of OncologyHospital of Chengdu University of Traditional Chinese MedicineChengduChina
| | - Hengyi Wang
- Department of Infectious DiseasesHospital of Chengdu University of Traditional Chinese MedicineChengduChina
| | - Lu Liu
- School of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Yulin Qi
- Department of OphthalmologyThe First Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou University of Chinese MedicineGuangzhouChina
- Postdoctoral Research Station of Guangzhou University of Chinese MedicineGuangzhouChina
| | - Shiyun Tang
- Hospital of Chengdu University of Traditional Chinese MedicineChengduChina
| | - Jianyuan Tang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan ProvinceHospital of Chengdu University of Traditional Chinese MedicineChengduChina
| | - Nianzhi Chen
- State Key Laboratory of Ultrasound in Medicine and EngineeringCollege of Biomedical EngineeringChongqing Medical UniversityChongqingChina
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11
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Hetmann A, Szymczak B, Czarnecka J, Rusak T, Wiśniewski M, Wujak M, Roszek K. Adenylate kinase immobilized on graphene oxide impairs progression of human lung carcinoma epithelial cells through adenosinergic pathway. J Biomed Mater Res A 2023; 111:1565-1576. [PMID: 37162101 DOI: 10.1002/jbm.a.37555] [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: 01/04/2023] [Revised: 04/04/2023] [Accepted: 04/26/2023] [Indexed: 05/11/2023]
Abstract
Purinergic signaling, the oldest evolutionary transmitter system, has been increasingly studied as a pivotal target for novel anti-cancer therapies. In the present work, the developed nanobiocatalytic system consisting of adenylate kinase immobilized on graphene oxide (AK-GO) was characterized in terms of its physicochemical and biochemical properties. We put special emphasis on the AK-GO influence on purinergic signaling components, that is, ecto-nucleotides concentration and ecto-enzymes expression and activity in human lung carcinoma epithelial (A549) cells. The immobilization-dependent modification of AK kinetic parameters allowed for the removal of ATP excess while maintaining low ATP concentrations, efficient decrease in adenosine concentration, and control of the nucleotide balance in carcinoma cells. The cyto- and hemocompatibility of developed AK-GO nanobiocatalytic system indicates that it can be successfully harnessed for biomedical applications. In A549 cells treated with AK-GO nanobiocatalytic system, the significantly decreased adenosinergic signaling results in reduction of the proliferation and migration capability of cancer cells. This finding is particularly relevant in regard to AK-GO prospective anti-cancer applications.
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Affiliation(s)
- Anna Hetmann
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Bartosz Szymczak
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Joanna Czarnecka
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Tomasz Rusak
- Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Bialystok, Bialystok, Poland
| | - Marek Wiśniewski
- Department of Materials Chemistry, Adsorption and Catalysis, Faculty of Chemistry, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Magdalena Wujak
- Department of Medicinal Chemistry, Collegium Medicum in Bydgoszcz, Faculty of Pharmacy, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Katarzyna Roszek
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, Torun, Poland
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12
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Tang Y, Qiao C, Li Q, Zhu X, Zhao R, Peng X. Research Progress in the Relationship Between P2X7R and Cervical Cancer. Reprod Sci 2023; 30:823-834. [PMID: 35799022 DOI: 10.1007/s43032-022-01022-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 06/16/2022] [Indexed: 11/28/2022]
Abstract
Cervical cancer is one of the most common and serious tumors in women. Finding new biomarkers and therapeutic targets plays an important role in the diagnosis, prognosis, and treatment of cervical cancer. Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a purine ligand cation channel, activated by adenosine triphosphate (ATP). Studies have shown that P2X7R plays an important role in a variety of diseases and cancers. More and more studies have shown that P2X7R is also closely related to cervical cancer; therefore, the role of P2X7R in the development of cervical cancer deserves further discussion. The expression level of P2X7R in uterine epithelial cancer tissues was lower than that of the corresponding normal tissues. P2X7R plays an important role in the apoptotic process of cervical cancer through various mechanisms of action, and both antagonists and agonists of P2X7R can inhibit the proliferation of cervical cancer cells, while P2X7R is involved in the antitumor effect of Atr-I on cervical cancer cells. This review evaluates the current role of P2X7R in cervical cancer in order to develop more specific therapies for cervical cancer. In conclusion, P2X7R may become a biomarker for cervical cancer screening, and even a new target for clinical treatment of cervical cancer.
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Affiliation(s)
- Yiqing Tang
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Cuicui Qiao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Qianqian Li
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Xiaodi Zhu
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Ronglan Zhao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China.
| | - Xiaoxiang Peng
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China.
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13
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Kaur J, Dora S. Purinergic signaling: Diverse effects and therapeutic potential in cancer. Front Oncol 2023; 13:1058371. [PMID: 36741002 PMCID: PMC9889871 DOI: 10.3389/fonc.2023.1058371] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
Regardless of improved biological insights and therapeutic advances, cancer is consuming multiple lives worldwide. Cancer is a complex disease with diverse cellular, metabolic, and physiological parameters as its hallmarks. This instigates a need to uncover the latest therapeutic targets to advance the treatment of cancer patients. Purines are building blocks of nucleic acids but also function as metabolic intermediates and messengers, as part of a signaling pathway known as purinergic signaling. Purinergic signaling comprises primarily adenosine triphosphate (ATP) and adenosine (ADO), their analogous membrane receptors, and a set of ectonucleotidases, and has both short- and long-term (trophic) effects. Cells release ATP and ADO to modulate cellular function in an autocrine or paracrine manner by activating membrane-localized purinergic receptors (purinoceptors, P1 and P2). P1 receptors are selective for ADO and have four recognized subtypes-A1, A2A, A2B, and A3. Purines and pyrimidines activate P2 receptors, and the P2X subtype is ligand-gated ion channel receptors. P2X has seven subtypes (P2X1-7) and forms homo- and heterotrimers. The P2Y subtype is a G protein-coupled receptor with eight subtypes (P2Y1/2/4/6/11/12/13/14). ATP, its derivatives, and purinoceptors are widely distributed in all cell types for cellular communication, and any imbalance compromises the homeostasis of the cell. Neurotransmission, neuromodulation, and secretion employ fast purinergic signaling, while trophic purinergic signaling regulates cell metabolism, proliferation, differentiation, survival, migration, invasion, and immune response during tumor progression. Thus, purinergic signaling is a prospective therapeutic target in cancer and therapy resistance.
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Affiliation(s)
- Jasmeet Kaur
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Sanchit Dora
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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14
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Suwara J, Radzikowska-Cieciura E, Chworos A, Pawlowska R. The ATP-dependent Pathways and Human Diseases. Curr Med Chem 2023; 30:1232-1255. [PMID: 35319356 DOI: 10.2174/0929867329666220322104552] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 12/31/2021] [Accepted: 01/04/2022] [Indexed: 11/22/2022]
Abstract
Adenosine triphosphate (ATP) is one of the most important molecules of life, present both inside the cells and extracellularly. It is an essential building block for nucleic acids biosynthesis and crucial intracellular energy storage. However, one of the most interesting functions of ATP is the role of a signaling molecule. Numerous studies indicate the involvement of ATP-dependent pathways in maintaining the proper functioning of individual tissues and organs. Herein, the latest data indicating the ATP function in the network of intra- and extracellular signaling pathways including purinergic signaling, MAP kinase pathway, mTOR and calcium signaling are collected. The main ATP-dependent processes maintaining the proper functioning of the nervous, cardiovascular and immune systems, as well as skin and bones, are summarized. The disturbances in the ATP amount, its cellular localization, or interaction with target elements may induce pathological changes in signaling pathways leading to the development of serious diseases. The impact of an ATP imbalance on the development of dangerous health dysfunctions such as neurodegeneration diseases, cardiovascular diseases (CVDs), diabetes mellitus, obesity, cancers and immune pathogenesis are discussed here.
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Affiliation(s)
- Justyna Suwara
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Lodz, Poland
| | - Ewa Radzikowska-Cieciura
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Lodz, Poland
| | - Arkadiusz Chworos
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Lodz, Poland
| | - Roza Pawlowska
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Lodz, Poland
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15
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Evers M, Song J, Shriwas P, Greenbaum HS, Chen X. From Transcriptomics, Metabolomics to Functional Studies: Extracellular ATP Induces TGF-β-Like Epithelial Mesenchymal Transition in Lung Cancer Cells. Front Oncol 2022; 12:912065. [PMID: 35847855 PMCID: PMC9282887 DOI: 10.3389/fonc.2022.912065] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/25/2022] [Indexed: 12/02/2022] Open
Abstract
We and others previously showed that extracellular ATP (eATP) is implicated in epithelial mesenchymal transition (EMT). However, the mechanisms by which eATP induces EMT and ATP’s relationship to TGF-β, a well-known EMT inducer, are largely unclear. Also, eATP-induced EMT has never been studied at transcriptomic and metabolomics levels. Based on our previous studies, we hypothesized that eATP acts as a specific inducer and regulator of EMT at all levels in cancer cells. RNAseq and metabolomics analyses were performed on human non-small cell lung cancer (NSCLC) A549 cells treated with either eATP or TGF-β. Bio-functional assays, such as invasion, intracellular ATP, cell proliferation, cytoskeleton remodeling, and others were conducted in NSCLC A549 and H1299 cells to validate changes observed from RNAseq and metabolomics studies. In the RNAseq study, eATP significantly enriched expressions of genes involved in EMT similarly to TGF-β after 2 and 6 hours of treatment. Samples treated with eATP for 2 hours share 131 upregulated EMT genes with those of TGF-β treated samples, and 42 genes at 6 hours treatment. Eleven genes, with known or unknown functions in EMT, are significantly upregulated by both inducers at both time points, have been identified. BLOC1S6, one of the 11 genes, was selected for further study. eATP induced numerous EMT-related changes in metabolic pathways, including cytoskeleton rearrangement, glycolysis, glutaminolysis, ROS, and individual metabolic changes similar to those induced by TGF-β. Functional bioassays verified the findings from RNAseq and metabolomics that eATP EMT-like changes in A549 and H1299 cells similarly to TGF-β. BLOC1S6 was found to be implicated in EMT. In these studies, eATP-induced EMT, at all levels examined, is similar but non-identical to that induced by TGF-β, and functions in such a way that exogenous addition of TGF-β is unnecessary for the induction. The study of BLOC1S6 further verified its potential roles in EMT and the RNAseq analysis results. All these strongly indicate that eATP is a multi-functional and multi-locational inducer and regulator of EMT, changing our thinking on how EMT is induced and regulated and pointing to new directions for inhibiting EMT in cancer.
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Affiliation(s)
- Maria Evers
- Honors Tutorial College, Ohio University, Athens, OH, United States
- The Ben May Department for Cancer Research, University of Chicago, Chicago, IL, United States
| | - Jingwen Song
- Department of Biological Sciences, Ohio University, Athens, OH, United States
- The Molecular and Cellular Biology Program, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
| | - Pratik Shriwas
- Department of Biological Sciences, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
| | - Harrison S. Greenbaum
- The Ben May Department for Cancer Research, University of Chicago, Chicago, IL, United States
| | - Xiaozhuo Chen
- Department of Biological Sciences, Ohio University, Athens, OH, United States
- The Molecular and Cellular Biology Program, Ohio University, Athens, OH, United States
- The Edison Biotechnology Institute, Ohio University, Athens, OH, United States
- Department of Biomedical Sciences, The Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
- *Correspondence: Xiaozhuo Chen,
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16
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Janho dit Hreich S, Benzaquen J, Hofman P, Vouret-Craviari V. The Purinergic Landscape of Non-Small Cell Lung Cancer. Cancers (Basel) 2022; 14:cancers14081926. [PMID: 35454832 PMCID: PMC9025794 DOI: 10.3390/cancers14081926] [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: 03/04/2022] [Revised: 04/06/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
Lung cancer is the most common cancer worldwide. Despite recent therapeutic advances, including targeted therapies and immune checkpoint inhibitors, the disease progresses in almost all advanced lung cancers and in up to 50% of early-stage cancers. The purpose of this review is to discuss whether purinergic checkpoints (CD39, CD73, P2RX7, and ADORs), which shape the immune response in the tumor microenvironment, may represent novel therapeutic targets to combat progression of non-small cell lung cancer by enhancing the antitumor immune response.
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Affiliation(s)
- Serena Janho dit Hreich
- Institute of Research on Cancer and Aging (IRCAN, CNRS, INSERM), FHU OncoAge, Université Côte d’Azur, 06108 Nice, France; (S.J.d.H.); (J.B.)
| | - Jonathan Benzaquen
- Institute of Research on Cancer and Aging (IRCAN, CNRS, INSERM), FHU OncoAge, Université Côte d’Azur, 06108 Nice, France; (S.J.d.H.); (J.B.)
| | - Paul Hofman
- CHU Nice, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Université Côte d’Azur, 06000 Nice, France;
- Institute of Research on Cancer and Aging (IRCAN, CNRS, INSERM, Team 4), Université Côte d’Azur, 06100 Nice, France
- CHU Nice, FHU OncoAge, Hospital-Integrated Biobank (BB-0033-00025), Université Côte d’Azur, 06000 Nice, France
| | - Valérie Vouret-Craviari
- Institute of Research on Cancer and Aging (IRCAN, CNRS, INSERM), FHU OncoAge, Université Côte d’Azur, 06108 Nice, France; (S.J.d.H.); (J.B.)
- Correspondence: ; Tel.: +33-492-031-223
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17
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Rotondo JC, Mazziotta C, Lanzillotti C, Stefani C, Badiale G, Campione G, Martini F, Tognon M. The Role of Purinergic P2X7 Receptor in Inflammation and Cancer: Novel Molecular Insights and Clinical Applications. Cancers (Basel) 2022; 14:1116. [PMID: 35267424 PMCID: PMC8909580 DOI: 10.3390/cancers14051116] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/09/2022] [Accepted: 02/17/2022] [Indexed: 12/11/2022] Open
Abstract
The purinergic P2X7 receptor (P2X7R) is a transmembrane protein whose expression has been related to a variety of cellular processes, while its dysregulation has been linked to inflammation and cancer. P2X7R is expressed in cancer and immune system cell surfaces. ATP plays a key role in numerous metabolic processes due to its abundance in the tumour microenvironment. P2X7R plays an important role in cancer by interacting with ATP. The unusual property of P2X7R is that stimulation with low doses of ATP causes the opening of a permeable channel for sodium, potassium, and calcium ions, whereas sustained stimulation with high doses of ATP favours the formation of a non-selective pore. The latter effect induces a change in intracellular homeostasis that leads to cell death. This evidence suggests that P2X7R has both pro- and anti-tumour proprieties. P2X7R is increasingly recognised as a regulator of inflammation. In this review, we aimed to describe the most relevant characteristics of P2X7R function, activation, and its ligands, while also summarising the role of P2X7R activation in the context of inflammation and cancer. The currently used therapeutic approaches and clinical trials of P2X7R modulators are also described.
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Affiliation(s)
- John Charles Rotondo
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
- Centre for Studies on Gender Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Chiara Mazziotta
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
- Centre for Studies on Gender Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Carmen Lanzillotti
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
- Centre for Studies on Gender Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Chiara Stefani
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
| | - Giada Badiale
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
| | - Giulia Campione
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
| | - Fernanda Martini
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
- Centre for Studies on Gender Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
- Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Mauro Tognon
- Laboratories of Cell Biology and Molecular Genetics, Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, 44121 Ferrara, Italy; (J.C.R.); (C.M.); (C.L.); (C.S.); (G.B.); (G.C.); (F.M.)
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18
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Bao L, Sun K, Zhang X. PANX1 is a potential prognostic biomarker associated with immune infiltration in pancreatic adenocarcinoma: A pan-cancer analysis. Channels (Austin) 2021; 15:680-696. [PMID: 34796785 PMCID: PMC8632293 DOI: 10.1080/19336950.2021.2004758] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Pannexin 1 (PANX1) channel is a critical ATP-releasing pathway that modulates tumor immunity, progression, and prognosis. However, the roles of PANX1 in different cancers remain unclear. We analyzed the expression of PANX1 in human pan-cancer in the Oncomine and GEPIA2.0 databases. The prognostic value of PANX1 expression was determined using Kaplan-Meier plotter and OncoLnc tools. The correlation between PANX1 and tumor-infiltrating immune cells was investigated using the TIMER 2.0. In addition, the relationship between PANX1 and immunomodulators was explored using TISIDB. Finally, gene set enrichment analysis (GSEA) was performed utilizing LinkedOmics. The results indicated that PANX1 was overexpressed in most cancers compared to normal tissues. The high expression of PANX1 was associated with poor prognosis in multiple tumors, especially in pancreatic adenocarcinoma (PAAD). In addition, PANX1 was correlated with a variety of immunomodulators, such as CD274, IL10, CD276, IL2RA, TAP1, and TAP2. PANX1 expression level was significantly related to infiltration of multiple immune cells in many cancers, including cancer associated fibroblast, macrophage, and neutrophil cells. Further analysis revealed that PANX1 was significantly associated with T cells CD8+ (rho = 0.524, P = 1.94e-13) and Myeloid dendritic cell (rho = 0.564, P = 9.45e-16). GSEA results showed that PANX1 was closely associated with leukocyte cell-cell adhesion, endoplasmic reticulum lumen, ECM-receptor interaction, and Focal adhesion pathways in PAAD. PANX1 expression was higher in pan-cancer samples than in normal tissues. The high expression of PANX1 was associated with poor outcome and immune infiltration in multiple cancers, especially in PAAD.
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Affiliation(s)
- Lingling Bao
- Department of Hematology and Oncology, Beilun District People's Hospital, Ningbo, Zhejiang, China
| | - Kai Sun
- Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Xuede Zhang
- Department of Hematology and Oncology, Beilun District People's Hospital, Ningbo, Zhejiang, China
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19
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Reyna-Jeldes M, Díaz-Muñoz M, Madariaga JA, Coddou C, Vázquez-Cuevas FG. Autocrine and paracrine purinergic signaling in the most lethal types of cancer. Purinergic Signal 2021; 17:345-370. [PMID: 33982134 PMCID: PMC8410929 DOI: 10.1007/s11302-021-09785-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer comprises a collection of diseases that occur in almost any tissue and it is characterized by an abnormal and uncontrolled cell growth that results in tumor formation and propagation to other tissues, causing tissue and organ malfunction and death. Despite the undeniable improvement in cancer diagnostics and therapy, there is an urgent need for new therapeutic and preventive strategies with improved efficacy and fewer side effects. In this context, purinergic signaling emerges as an interesting candidate as a cancer biomarker or therapeutic target. There is abundant evidence that tumor cells have significant changes in the expression of purinergic receptors, which comprise the G-protein coupled P2Y and AdoR families of receptors and the ligand-gated ion channel P2X receptors. Tumor cells also exhibit changes in the expression of nucleotidases and other enzymes involved in nucleotide metabolism, and the concentrations of extracellular nucleotides are significantly higher than those observed in normal cells. In this review, we will focus on the potential role of purinergic signaling in the ten most lethal cancers (lung, breast, colorectal, liver, stomach, prostate, cervical, esophagus, pancreas, and ovary), which together are responsible for more than 5 million annual deaths.
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Affiliation(s)
- M Reyna-Jeldes
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
- Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago, Chile
- Núcleo para el Estudio del Cáncer a nivel Básico, Aplicado y Clínico, Universidad Católica del Norte, Antofagasta, Chile
| | - M Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Querétaro, México
| | - J A Madariaga
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
- Núcleo para el Estudio del Cáncer a nivel Básico, Aplicado y Clínico, Universidad Católica del Norte, Antofagasta, Chile
| | - C Coddou
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile.
- Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago, Chile.
- Núcleo para el Estudio del Cáncer a nivel Básico, Aplicado y Clínico, Universidad Católica del Norte, Antofagasta, Chile.
| | - F G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Querétaro, México.
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20
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Sharma A, Ramena GT, Elble RC. Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy. Biomedicines 2021; 9:1077. [PMID: 34572262 PMCID: PMC8466575 DOI: 10.3390/biomedicines9091077] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/15/2021] [Accepted: 07/18/2021] [Indexed: 02/07/2023] Open
Abstract
Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them to signaling hubs needing the cations. Ca2+ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca2+ repositories. Cellular Ca2+ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca2+ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca2+ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca2+ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area.
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Affiliation(s)
- Aarushi Sharma
- Department of Pharmacology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
| | - Grace T. Ramena
- Department of Aquaculture, University of Arkansas, Pine Bluff, AR 71601, USA;
| | - Randolph C. Elble
- Department of Pharmacology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
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21
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Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines. Pharmaceutics 2021; 13:pharmaceutics13081234. [PMID: 34452195 PMCID: PMC8398939 DOI: 10.3390/pharmaceutics13081234] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/07/2021] [Accepted: 08/09/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is a major health concern worldwide, presenting a complex pathophysiology that has hindered many therapeutic efforts so far. In this context, purinergic signaling emerges as a promising pathway for intervention due to its known role in cancer cell proliferation and migration. In this work, we explored in more detail the role of purinergic signaling in GC with several experimental approaches. First, we measured extracellular ATP concentrations on GC-derived cell lines (AGS, MKN-45, and MKN-74), finding higher levels of extracellular ATP than those obtained for the non-tumoral gastric cell line GES-1. Next, we established the P2Y2 and P2X4 receptors (P2Y2R and P2X4R) expression profile on these cells and evaluated their role on cell proliferation and migration after applying overexpression and knockdown strategies. In general, a P2Y2R overexpression and P2X4R downregulation pattern were observed on GC cell lines, and when these patterns were modified, concomitant changes in cell viability were observed. These modifications on gene expression also modified transepithelial electrical resistance (TEER), showing that higher P2Y2R levels decreased TEER, and high P2X4R expression had the opposite effect, suggesting that P2Y2R and P2X4R activation could promote and suppress epithelial-mesenchymal transition (EMT), respectively. These effects were confirmed after treating AGS cells with UTP, a P2Y2R-agonist that modified the expression patterns towards mesenchymal markers. To further characterize the effects of P2Y2R activation on EMT, we used cDNA microarrays and observed that UTP induced important transcriptional changes on several cell processes like cell proliferation induction, apoptosis inhibition, cell differentiation induction, and cell adhesion reduction. These results suggest that purinergic signaling plays a complex role in GC pathophysiology, and changes in purinergic balance can trigger tumorigenesis in non-tumoral gastric cells.
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22
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Pannexin1: Role as a Sensor to Injury Is Attenuated in Pretype 2 Corneal Diabetic Epithelium. ACTA ACUST UNITED AC 2021; 2021:4793338. [PMID: 34336553 PMCID: PMC8295002 DOI: 10.1155/2021/4793338] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/07/2021] [Indexed: 11/17/2022]
Abstract
Epithelial wound healing is essential to repair the corneal barrier function after injury and requires coordinated epithelial sheet movement over the wounded region. The presence and role of pannexin1 on multilayered epithelial sheet migration was examined in unwounded and wounded corneal epithelium from C57BL/6J (B6) control and diet-induced obese (DiO) mice, a pretype 2 diabetic model. We hypothesize that pannexin1 is dysregulated, and the interaction of two ion-channel proteins (P2X7 and pannexin1) is altered in pretype 2 diabetic tissue. Pannexin1 was found to be present along cell borders in unwounded tissue, and no significant difference was observed between DiO and B6 control. However, an epithelial debridement induced a striking difference in pannexin1 localization. The B6 control epithelium displayed intense staining near the leading edge, which is the region where calcium mobilization was detected, whereas the staining in the DiO corneal epithelium was diffuse and lacked distinct gradation in intensity back from the leading edge. Cells distal to the wound in the DiO tissue were irregular in shape, and the morphology was similar to that of epithelium inhibited with 10Panx, a pannexin1 inhibitor. Pannexin1 inhibition reduced mobilization of calcium between cells near the leading edge, and MATLAB scripts revealed a reduction in cell-cell communication that was also detected in cultured cells. Proximity ligation was performed to determine if P2X7 and pannexin1 interaction was a necessary component of motility and communication. While there was no significant difference in the interaction in unwounded DiO and B6 control corneal epithelium, there was significantly less interaction in the wounded DiO corneas both near the wound and back from the edge. The results demonstrate that pannexin1 contributes to the healing response, and P2X7 and pannexin1 coordination may be a required component of cell-cell communication and an underlying reason for the lack of pathologic tissue migration.
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23
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Zhang WJ. Effect of P2X purinergic receptors in tumor progression and as a potential target for anti-tumor therapy. Purinergic Signal 2021; 17:151-162. [PMID: 33420658 PMCID: PMC7954979 DOI: 10.1007/s11302-020-09761-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
The development of tumors is a complex pathological process involving multiple factors, multiple steps, and multiple genes. Their prevention and treatment have always been a difficult problem at present. A large number of studies have proved that the tumor microenvironment plays an important role in the progression of tumors. The tumor microenvironment is the place where tumor cells depend for survival, and it plays an important role in regulating the growth, proliferation, apoptosis, migration, and invasion of tumor cells. P2X purinergic receptors, which depend on the ATP ion channel, can be activated by ATP in the tumor microenvironment, and by mediating tumor cells and related cells (such as immune cells) in the tumor microenvironment. They play an important regulatory role on the effects of the skeleton, membrane fluidity, and intracellular molecular metabolism of tumor cells. Therefore, here, we outlined the biological characteristics of P2X purinergic receptors, described the effect of tumor microenvironment on tumor progression, and discussed the effect of ATP on tumor. Moreover, we explored the role of P2X purinergic receptors in the development of tumors and anti-tumor therapy. These data indicate that P2X purinergic receptors may be used as another potential pharmacological target for tumor prevention and treatment.
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Affiliation(s)
- Wen-Jun Zhang
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang, 343000, Jiangxi, China.
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24
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Dutot M, Olivier E, Fouyet S, Magny R, Hammad K, Roulland E, Rat P, Fagon R. In Vitro Chemopreventive Potential of Phlorotannins-Rich Extract from Brown Algae by Inhibition of Benzo[a]pyrene-Induced P2X7 Activation and Toxic Effects. Mar Drugs 2021; 19:34. [PMID: 33466689 PMCID: PMC7828825 DOI: 10.3390/md19010034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 12/15/2022] Open
Abstract
Phlorotannins are polyphenols occurring exclusively in some species of brown algae, known for numerous biological activities, e.g., antioxidant, antiproliferative, antidiabetic, and antiallergic properties. Their effects on the response of human lung cells to benzo[a]pyrene (B[a]P) has not been characterized. Our objective was to in vitro evaluate the effects of a phlorotannin-rich extract obtained from the brown algae Ascophyllum nodosum and Fucus vesiculosus on B[a]P cytotoxic effects. The A549 cell line was incubated with B[a]P for 48 and 72 h in the presence or absence of the brown algae extract. Cytochrome P450 activity, activation of P2X7 receptor, F-actin disorganization, and loss of E-cadherin expression were assessed using microplate cytometry and fluorescence microscopy. Relative to control, incubation with the brown algae extract was associated with lower B[a]P-induced CYP1 activity, lower P2X7 receptor activation, and lower reactive oxygen species production. The brown algae extract inhibited the alterations of F-actin arrangement and the downregulation of E-cadherin expression. We identified a phlorotannins-rich extract that could be deeper investigated as a cancer chemopreventive agent to block B[a]P-mediated carcinogenesis.
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Affiliation(s)
- Mélody Dutot
- Recherche & Développement, Yslab, 29000 Quimper, France;
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Elodie Olivier
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Sophie Fouyet
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Romain Magny
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Karim Hammad
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Emmanuel Roulland
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Patrice Rat
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Roxane Fagon
- Recherche & Développement, Yslab, 29000 Quimper, France;
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25
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Purinergic Signaling Within the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1270:73-87. [PMID: 33123994 DOI: 10.1007/978-3-030-47189-7_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Accumulating studies have clearly demonstrated high concentrations of extracellular ATP (eATP) within the tumor microenvironment (TME). Implications of these findings are multifold as ATP-mediated purinergic signaling has been shown to mediate a variety of cancer-related processes, including cell migration, resistance to cytotoxic therapy, and immune regulation. Broad roles of ATP within the tumor microenvironment are linked to the abundance of ATP-regulated purinergic receptors on cancer and stromal and various immune cell types, as well as on the importance of ATP release and signaling in the regulation of multiple cellular processes. ATP release and downstream purinergic signaling are emerging as a central regulator of tumor growth and an important target for therapeutic intervention. In this chapter, we summarize the major roles of purinergic signaling in the tumor microenvironment with a specific focus on its critical roles in the induction of immunogenic cancer cell death and immune modulation.
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26
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Brenet M, Martínez S, Pérez-Nuñez R, Pérez LA, Contreras P, Díaz J, Avalos AM, Schneider P, Quest AFG, Leyton L. Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca 2+/P2X7 Receptor Signaling Axis. Front Cell Dev Biol 2021; 8:592442. [PMID: 33511115 PMCID: PMC7835543 DOI: 10.3389/fcell.2020.592442] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 12/04/2020] [Indexed: 01/21/2023] Open
Abstract
Cancer cell adhesion to the vascular endothelium is an important step in tumor metastasis. Thy-1 (CD90), a cell adhesion molecule expressed in activated endothelial cells, has been implicated in melanoma metastasis by binding to integrins present in cancer cells. However, the signaling pathway(s) triggered by this Thy-1-Integrin interaction in cancer cells remains to be defined. Our previously reported data indicate that Ca2+-dependent hemichannel opening, as well as the P2X7 receptor, are key players in Thy-1-αVβ3 Integrin-induced migration of reactive astrocytes. Thus, we investigated whether this signaling pathway is activated in MDA-MB-231 breast cancer cells and in B16F10 melanoma cells when stimulated with Thy-1. In both cancer cell types, Thy-1 induced a rapid increase in intracellular Ca2+, ATP release, as well as cell migration and invasion. Connexin and Pannexin inhibitors decreased cell migration, implicating a requirement for hemichannel opening in Thy-1-induced cell migration. In addition, cell migration and invasion were precluded when the P2X7 receptor was pharmacologically blocked. Moreover, the ability of breast cancer and melanoma cells to transmigrate through an activated endothelial monolayer was significantly decreased when the β3 Integrin was silenced in these cancer cells. Importantly, melanoma cells with silenced β3 Integrin were unable to metastasize to the lung in a preclinical mouse model. Thus, our results suggest that the Ca2+/hemichannel/ATP/P2X7 receptor-signaling axis triggered by the Thy-1-αVβ3 Integrin interaction is important for cancer cell migration, invasion and transvasation. These findings open up the possibility of therapeutically targeting the Thy-1-Integrin signaling pathway to prevent metastasis.
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Affiliation(s)
- Marianne Brenet
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Samuel Martínez
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Ramón Pérez-Nuñez
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Leonardo A Pérez
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Pamela Contreras
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Jorge Díaz
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Ana María Avalos
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Pascal Schneider
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Andrew F G Quest
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Lisette Leyton
- Cellular Communication Laboratory, Program of Cellular & Molecular Biology, Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
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27
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Schilpp C, Lochbaum R, Braubach P, Jonigk D, Frick M, Dietl P, Wittekindt OH. TGF-β1 increases permeability of ciliated airway epithelia via redistribution of claudin 3 from tight junction into cell nuclei. Pflugers Arch 2021; 473:287-311. [PMID: 33386991 PMCID: PMC7835204 DOI: 10.1007/s00424-020-02501-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 10/31/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023]
Abstract
TGF-β1 is a major mediator of airway tissue remodelling during atopic asthma and affects tight junctions (TJs) of airway epithelia. However, its impact on TJs of ciliated epithelia is sparsely investigated. Herein we elaborated effects of TGF-β1 on TJs of primary human bronchial epithelial cells. We demonstrate that TGF-β1 activates TGF-β1 receptors TGFBR1 and TGFBR2 resulting in ALK5-mediated phosphorylation of SMAD2. We observed that TGFBR1 and -R2 localize specifically on motile cilia. TGF-β1 activated accumulation of phosphorylated SMAD2 (pSMAD2-C) at centrioles of motile cilia and at cell nuclei. This triggered an increase in paracellular permeability via cellular redistribution of claudin 3 (CLDN3) from TJs into cell nuclei followed by disruption of epithelial integrity and formation of epithelial lesions. Only ciliated cells express TGF-β1 receptors; however, nuclear accumulations of pSMAD2-C and CLDN3 redistribution were observed with similar time course in ciliated and non-ciliated cells. In summary, we demonstrate a role of motile cilia in TGF-β1 sensing and showed that TGF-β1 disturbs TJ permeability of conductive airway epithelia by redistributing CLDN3 from TJs into cell nuclei. We conclude that the observed effects contribute to loss of epithelial integrity during atopic asthma.
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Affiliation(s)
- Carolin Schilpp
- Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany
| | - Robin Lochbaum
- Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany
| | - Peter Braubach
- Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Danny Jonigk
- Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Manfred Frick
- Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany
| | - Paul Dietl
- Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany
| | - Oliver H Wittekindt
- Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
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28
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Systematic alteration of in vitro metabolic environments reveals empirical growth relationships in cancer cell phenotypes. Cell Rep 2021; 34:108647. [PMID: 33472066 PMCID: PMC7877896 DOI: 10.1016/j.celrep.2020.108647] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/15/2020] [Accepted: 12/22/2020] [Indexed: 01/01/2023] Open
Abstract
Cancer cells, like microbes, live in complex metabolic environments. Recent evidence suggests that microbial behavior across metabolic environments is well described by simple empirical growth relationships, or growth laws. Do such empirical growth relationships also exist in cancer cells? To test this question, we develop a high-throughput approach to extract quantitative measurements of cancer cell behaviors in systematically altered metabolic environments. Using this approach, we examine relationships between growth and three frequently studied cancer phenotypes: drug-treatment survival, cell migration, and lactate overflow. Drug-treatment survival follows simple linear growth relationships, which differ quantitatively between chemotherapeutics and EGFR inhibition. Cell migration follows a weak grow-and-go growth relationship, with substantial deviation in some environments. Finally, lactate overflow is mostly decoupled from growth rate and is instead determined by the cells’ ability to maintain high sugar uptake rates. Altogether, this work provides a quantitative approach for formulating empirical growth laws of cancer. Kochanowski et al. quantify cancer cell phenotypes across systematically altered in vitro metabolic environments to search for phenotype-growth relationships, similar to the growth laws found in microbes. Three case studies highlight examples in which such growth relationships are clearly operating (cancer drug survival), weakly present (cell migration), or absent (lactate overflow).
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Zhang WJ, Hu CG, Luo HL, Zhu ZM. Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling. Front Cell Dev Biol 2020; 8:586555. [PMID: 33330466 PMCID: PMC7732635 DOI: 10.3389/fcell.2020.586555] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/26/2020] [Indexed: 12/18/2022] Open
Abstract
The pathological mechanism of colon cancer is very complicated. Therefore, exploring the molecular basis of the pathogenesis of colon cancer and finding a new therapeutic target has become an urgent problem to be solved in the treatment of colon cancer. ATP plays an important role in regulating the progression of tumor cells. P2 × 7 belongs to ATP ion channel receptor, which is involved in the progression of tumors. In this study, we explored the effect and molecular mechanism of ATP-mediated P2 × 7 receptor on the migration and metastasis of colon cancer cells. The results showed that ATP and BzATP significantly increased the inward current and intracellular calcium concentration of LOVO and SW480 cells, while the use of antagonists (A438079 and AZD9056) could reverse the above phenomenon. We found that ATP promoted the migration and invasion of LOVO and SW480 cells and is dose-dependent on ATP concentration (100–300 μM). Similarly, BzATP (10, 50, and 100 μM) also significantly promoted the migration and invasion of colon cancer cells in a concentration-dependent manner. While P2 × 7 receptor antagonists [A438079 (10 μM), AZD9056 (10 μM)] or P2 × 7 siRNA could significantly inhibit ATP-induced colon cancer cell migration and invasion. Moreover, in vivo experiments showed that ATP-induced activation of P2 × 7 receptor promoted the growth of tumors. Furthermore, P2 × 7 receptor activation down-regulated E-cadherin protein expression and up-regulated MMP-2 mRNA and concentration levels. Knocking down the expression of P2 × 7 receptor could significantly inhibit the increase in the expression of N-cadherin, Vimentin, Zeb1, and Snail induced by ATP. In addition, ATP time-dependently induced the activation of STAT3 via the P2 × 7 receptor, and the STAT3 pathway was required for the ATP-mediated invasion and migration. Our conclusion is that ATP-induced P2 × 7 receptor activation promotes the migration and invasion of colon cancer cells, possibly via the activation of STAT3 pathway. Therefore, the P2 × 7 receptor may be a potential target for the treatment of colon cancer.
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Affiliation(s)
- Wen-Jun Zhang
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Ce-Gui Hu
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Hong-Liang Luo
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Zheng-Ming Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
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30
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Novak I, Yu H, Magni L, Deshar G. Purinergic Signaling in Pancreas-From Physiology to Therapeutic Strategies in Pancreatic Cancer. Int J Mol Sci 2020; 21:E8781. [PMID: 33233631 PMCID: PMC7699721 DOI: 10.3390/ijms21228781] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
The purinergic signaling has an important role in regulating pancreatic exocrine secretion. The exocrine pancreas is also a site of one of the most serious cancer forms, the pancreatic ductal adenocarcinoma (PDAC). Here, we explore how the network of purinergic and adenosine receptors, as well as ecto-nucleotidases regulate normal pancreatic cells and various cells within the pancreatic tumor microenvironment. In particular, we focus on the P2X7 receptor, P2Y2 and P2Y12 receptors, as well as A2 receptors and ecto-nucleotidases CD39 and CD73. Recent studies indicate that targeting one or more of these candidates could present new therapeutic approaches to treat pancreatic cancer. In pancreatic cancer, as much as possible of normal pancreatic function should be preserved, and therefore physiology of purinergic signaling in pancreas needs to be considered.
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MESH Headings
- 5'-Nucleotidase/genetics
- 5'-Nucleotidase/immunology
- Animals
- Antibodies, Monoclonal/therapeutic use
- Antineoplastic Agents, Immunological/therapeutic use
- Apyrase/genetics
- Apyrase/immunology
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/pathology
- Clinical Trials as Topic
- GPI-Linked Proteins/genetics
- GPI-Linked Proteins/immunology
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/immunology
- Humans
- Immunotherapy/methods
- Pancreas/drug effects
- Pancreas/immunology
- Pancreas/pathology
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/pathology
- Pancreatic Stellate Cells/drug effects
- Pancreatic Stellate Cells/immunology
- Pancreatic Stellate Cells/pathology
- Receptors, Adenosine A2/genetics
- Receptors, Adenosine A2/immunology
- Receptors, Purinergic P2X7/genetics
- Receptors, Purinergic P2X7/immunology
- Receptors, Purinergic P2Y12/genetics
- Receptors, Purinergic P2Y12/immunology
- Receptors, Purinergic P2Y2/genetics
- Receptors, Purinergic P2Y2/immunology
- Signal Transduction/genetics
- Signal Transduction/immunology
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
- Ivana Novak
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen Ø, Denmark; (H.Y.); (L.M.); (G.D.)
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31
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Extracellular ATP: A Feasible Target for Cancer Therapy. Cells 2020; 9:cells9112496. [PMID: 33212982 PMCID: PMC7698494 DOI: 10.3390/cells9112496] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 12/22/2022] Open
Abstract
Adenosine triphosphate (ATP) is one of the main biochemical components of the tumor microenvironment (TME), where it can promote tumor progression or tumor suppression depending on its concentration and on the specific ecto-nucleotidases and receptors expressed by immune and cancer cells. ATP can be released from cells via both specific and nonspecific pathways. A non-regulated release occurs from dying and damaged cells, whereas active release involves exocytotic granules, plasma membrane-derived microvesicles, specific ATP-binding cassette (ABC) transporters and membrane channels (connexin hemichannels, pannexin 1 (PANX1), calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs) and maxi-anion channels (MACs)). Extracellular ATP acts at P2 purinergic receptors, among which P2X7R is a key mediator of the final ATP-dependent biological effects. Over the years, P2 receptor- or ecto-nucleotidase-targeting for cancer therapy has been proposed and actively investigated, while comparatively fewer studies have explored the suitability of TME ATP as a target. In this review, we briefly summarize the available evidence suggesting that TME ATP has a central role in determining tumor fate and is, therefore, a suitable target for cancer therapy.
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32
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Pelleg A. Extracellular adenosine 5'-triphosphate in pulmonary disorders. Biochem Pharmacol 2020; 187:114319. [PMID: 33161021 DOI: 10.1016/j.bcp.2020.114319] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 02/06/2023]
Abstract
Adenosine 5'-triphosphate (ATP) is found in every cell of the human body where it plays a critical role in cellular energetics and metabolism. ATP is released from cells under physiologic and pathophysiologic condition; extracellular ATP is rapidly degraded to adenosine 5'-diphosphate (ADP) and adenosine by ecto-enzymes (mainly, CD39 and CD73). Before its degradation, ATP acts as an autocrine and paracrine agent exerting its effects on targeted cells by activating cell surface receptors named P2 Purinergic receptors. The latter are expressed by different cell types in the lungs, the activation of which is involved in multiple pulmonary disorders. This succinct review summarizes the role of ATP in inflammation processes associated with these disorders including bronchoconstriction, cough, mechanical ventilation-induced lung injury and idiopathic pulmonary fibrosis. All of these disorders still constitute unmet clinical needs. Therefore, the various ATP-signaling pathways in pulmonary inflammation constitute attractive targets for novel drug-candidates that would improve the management of patients with multiple pulmonary diseases.
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Affiliation(s)
- Amir Pelleg
- Danmir Therapeutics, LLC, Haverford, PA, USA. http://www.danmirtherapeutics.com
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33
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The P2X7 purinergic receptor: a potential therapeutic target for lung cancer. J Cancer Res Clin Oncol 2020; 146:2731-2741. [PMID: 32892231 DOI: 10.1007/s00432-020-03379-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 09/01/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Purinergic P2X7 receptor (P2X7R) is a gated ion channel for which adenosine triphosphate (ATP) is a ligand. Activated P2X7R is widely expressed in a variety of immune cells and tissues and is involved in a variety of physiological and pathological processes. Studies have confirmed that P2X7R is involved in the regulation of tumor cell growth, stimulating cell proliferation or inducing apoptosis. Recent studies have found that P2X7R is abnormally expressed in lung cancer and is closely related to the carcinogenesis and development of lung cancer. In this paper, we comprehensively describe the structure, function, and genetic polymorphisms of P2X7R. In particular, the role and therapeutic potential of P2X7R in lung cancer are discussed to provide new targets and new strategies for the treatment and prognosis of clinical lung cancer. METHODS The relevant literature on P2X7R and lung cancer from PubMed databases is reviewed in this article. RESULTS P2X7R regulates the function of lung cancer cells by activating multiple intracellular signaling pathways (such as the JNK, Rho, HMGB1 and EMT pathways), thereby affecting cell survival, growth, invasion, and metastasis and patient prognosis. Targeting P2X7R with inhibitors effectively suppresses the growth and metastasis of lung cancer cells. CONCLUSION In summary, P2X7R is expected to become a potential target for the treatment of lung cancer, and more clinical research is needed in the future to explore the effectiveness of P2X7R antagonists as treatments.
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34
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Brisson L, Chadet S, Lopez-Charcas O, Jelassi B, Ternant D, Chamouton J, Lerondel S, Le Pape A, Couillin I, Gombault A, Trovero F, Chevalier S, Besson P, Jiang LH, Roger S. P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment. Cancers (Basel) 2020; 12:cancers12092342. [PMID: 32825056 PMCID: PMC7565976 DOI: 10.3390/cancers12092342] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/12/2020] [Accepted: 08/17/2020] [Indexed: 12/20/2022] Open
Abstract
The P2X7 receptor is an ATP-gated cation channel with a still ambiguous role in cancer progression, proposed to be either pro- or anti-cancerous, depending on the cancer or cell type in the tumour. Its role in mammary cancer progression is not yet defined. Here, we show that P2X7 receptor is functional in highly aggressive mammary cancer cells, and induces a change in cell morphology with fast F-actin reorganization and formation of filopodia, and promotes cancer cell invasiveness through both 2- and 3-dimensional extracellular matrices in vitro. Furthermore, P2X7 receptor sustains Cdc42 activity and the acquisition of a mesenchymal phenotype. In an immunocompetent mouse mammary cancer model, we reveal that the expression of P2X7 receptor in cancer cells, but not in the host mice, promotes tumour growth and metastasis development, which were reduced by treatment with specific P2X7 antagonists. Our results demonstrate that P2X7 receptor drives mammary tumour progression and represents a pertinent target for mammary cancer treatment.
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Affiliation(s)
- Lucie Brisson
- Inserm UMR1069-Nutrition, Growth and Cancer, University of Tours, 37032 Tours, France; (L.B.); (J.C.); (S.C.)
| | - Stéphanie Chadet
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Osbaldo Lopez-Charcas
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Bilel Jelassi
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - David Ternant
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Julie Chamouton
- Inserm UMR1069-Nutrition, Growth and Cancer, University of Tours, 37032 Tours, France; (L.B.); (J.C.); (S.C.)
| | - Stéphanie Lerondel
- CNRS UPS44 TAAM, PHENOMIN, Centre d’Imagerie du Petit Animal, 45071 Orléans, France; (S.L.); (A.L.P.)
| | - Alain Le Pape
- CNRS UPS44 TAAM, PHENOMIN, Centre d’Imagerie du Petit Animal, 45071 Orléans, France; (S.L.); (A.L.P.)
| | - Isabelle Couillin
- Laboratory of Molecular and Experimental Immunology and Neurogenetics, UMR 7355, CNRS, University of Orléans, 45071 Orléans, France; (I.C.); (A.G.)
| | - Aurélie Gombault
- Laboratory of Molecular and Experimental Immunology and Neurogenetics, UMR 7355, CNRS, University of Orléans, 45071 Orléans, France; (I.C.); (A.G.)
| | | | - Stéphan Chevalier
- Inserm UMR1069-Nutrition, Growth and Cancer, University of Tours, 37032 Tours, France; (L.B.); (J.C.); (S.C.)
| | - Pierre Besson
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Lin-Hua Jiang
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
- Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang 453003, China
| | - Sébastien Roger
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
- Institut Universitaire de France, 75005 Paris, France
- Correspondence: ; Tel.: +33-2-47-36-61-30
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35
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da Silva Ferreira NC, Alves LA, Soares-Bezerra RJ. Potential Therapeutic Applications of P2 Receptor Antagonists: From Bench to Clinical Trials. Curr Drug Targets 2020; 20:919-937. [PMID: 30760187 DOI: 10.2174/1389450120666190213095923] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 01/30/2019] [Accepted: 02/06/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Extracellular purines and pyrimidines have important physiological functions in mammals. Purines and pyrimidines act on P1 and P2 purinergic receptors, which are widely expressed in the plasma membrane in various cell types. P2 receptors act as important therapeutic targets and are associated with several disorders, such as pain, neurodegeneration, cancer, inflammation, and thrombosis. However, the use of antagonists for P2 receptors in clinical therapy, with the exception of P2Y12, is a great challenge. Currently, many research groups and pharmaceutical companies are working on the development of specific antagonist molecules for each receptor subtype that could be used as new medicines to treat their respective disorders. OBJECTIVE The present review compiles some interesting findings on the application of P2 receptor antagonists in different in vitro and in vivo experimental models as well as the progress of advanced clinical trials with these compounds. CONCLUSION Despite all of the exciting results obtained on the bench, few antagonists of P2 receptors advanced to the clinical trials, and once they reach this stage, the effectiveness of the therapy is not guaranteed, as in the example of P2X7 antagonists. Despite this, P2Y12 receptor antagonists have a history of success and have been used in therapy for at least two decades to prevent thrombosis in patients at risk for myocardial infarctions. This breakthrough is the motivation for scientists to develop new drugs with antagonistic activity for the other P2 receptors; thus, in a matter of years, we will have an evolution in the field of purinergic therapy.
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Affiliation(s)
- Natiele C da Silva Ferreira
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040- 360, Brazil
| | - Luiz A Alves
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040- 360, Brazil
| | - Rômulo J Soares-Bezerra
- Laboratory of Technological Development in Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040-360, Brazil
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36
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Aroua N, Boet E, Ghisi M, Nicolau-Travers ML, Saland E, Gwilliam R, de Toni F, Hosseini M, Mouchel PL, Farge T, Bosc C, Stuani L, Sabatier M, Mazed F, Larrue C, Jarrou L, Gandarillas S, Bardotti M, Picard M, Syrykh C, Laurent C, Gotanègre M, Bonnefoy N, Bellvert F, Portais JC, Nicot N, Azuaje F, Kaoma T, Joffre C, Tamburini J, Récher C, Vergez F, Sarry JE. Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia. Cancer Discov 2020; 10:1544-1565. [PMID: 32641297 DOI: 10.1158/2159-8290.cd-19-1008] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 05/09/2020] [Accepted: 07/02/2020] [Indexed: 11/16/2022]
Abstract
Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell-surface expression and activity is increased in patients with AML upon chemotherapy compared with diagnosis, and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes cytarabine resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adaptive mitochondrial stress response. Finally, genetic and pharmacologic inhibition of CD39 ecto-ATPase activity blocks the mitochondrial reprogramming triggered by cytarabine treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo. Together, these results reveal CD39 as a new residual disease marker and a promising therapeutic target to improve chemotherapy response in AML. SIGNIFICANCE: Extracellular ATP and CD39-P2RY13-cAMP-OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML.This article is highlighted in the In This Issue feature, p. 1426.
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Affiliation(s)
- Nesrine Aroua
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Emeline Boet
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Margherita Ghisi
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Marie-Laure Nicolau-Travers
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France.,Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France
| | - Estelle Saland
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Ryan Gwilliam
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Fabienne de Toni
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Mohsen Hosseini
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Pierre-Luc Mouchel
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France.,Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France
| | - Thomas Farge
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Claudie Bosc
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Lucille Stuani
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Marie Sabatier
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Fetta Mazed
- Institut Cochin, Département Développement, Reproduction, Cancer, UMR8104-CNRS, U1016-INSERM, Paris.,Translational Research Centre in Onco-Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Clément Larrue
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Latifa Jarrou
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Sarah Gandarillas
- Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales, Service d'Expérimentation Animale, UMS006, Inserm, Toulouse, France
| | - Massimiliano Bardotti
- Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales, Service d'Expérimentation Animale, UMS006, Inserm, Toulouse, France
| | - Muriel Picard
- University of Toulouse, Toulouse, France.,Intensive Care Unit, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France
| | - Charlotte Syrykh
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France.,Service d'Anatomopathologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France
| | - Camille Laurent
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France.,Service d'Anatomopathologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France
| | - Mathilde Gotanègre
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Nathalie Bonnefoy
- Institut de Recherche en Cancérologie de Montpellier, U1194, Inserm, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
| | | | | | - Nathalie Nicot
- LuxGene, Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Francisco Azuaje
- Computational Biomedicine Research Group, Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Tony Kaoma
- Computational Biomedicine Research Group, Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Carine Joffre
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France
| | - Jérome Tamburini
- Institut Cochin, Département Développement, Reproduction, Cancer, UMR8104-CNRS, U1016-INSERM, Paris.,Translational Research Centre in Onco-Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christian Récher
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France.,Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France
| | - François Vergez
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France.,University of Toulouse, Toulouse, France.,Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France
| | - Jean-Emmanuel Sarry
- Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Labellisée LIGUE 2018, Toulouse, France. .,University of Toulouse, Toulouse, France
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37
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Purinergic Signaling in the Hallmarks of Cancer. Cells 2020; 9:cells9071612. [PMID: 32635260 PMCID: PMC7407645 DOI: 10.3390/cells9071612] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/29/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.
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38
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Lara R, Adinolfi E, Harwood CA, Philpott M, Barden JA, Di Virgilio F, McNulty S. P2X7 in Cancer: From Molecular Mechanisms to Therapeutics. Front Pharmacol 2020; 11:793. [PMID: 32581786 PMCID: PMC7287489 DOI: 10.3389/fphar.2020.00793] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/13/2020] [Indexed: 12/18/2022] Open
Abstract
P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and post-translational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7.
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Affiliation(s)
- Romain Lara
- Biosceptre (UK) Limited, Cambridge, United Kingdom
| | - Elena Adinolfi
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Mike Philpott
- Centre for Cutaneous Research, Blizard Institute, Bart's & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | | | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
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Stokes L, Bidula S, Bibič L, Allum E. To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors? Front Pharmacol 2020; 11:627. [PMID: 32477120 PMCID: PMC7235284 DOI: 10.3389/fphar.2020.00627] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/21/2020] [Indexed: 12/15/2022] Open
Abstract
The family of ligand-gated ion channels known as P2X receptors were discovered several decades ago. Since the cloning of the seven P2X receptors (P2X1-P2X7), a huge research effort has elucidated their roles in regulating a range of physiological and pathophysiological processes. Transgenic animals have been influential in understanding which P2X receptors could be new therapeutic targets for disease. Furthermore, understanding how inherited mutations can increase susceptibility to disorders and diseases has advanced this knowledge base. There has been an emphasis on the discovery and development of pharmacological tools to help dissect the individual roles of P2X receptors and the pharmaceutical industry has been involved in pushing forward clinical development of several lead compounds. During the discovery phase, a number of positive allosteric modulators have been described for P2X receptors and these have been useful in assigning physiological roles to receptors. This review will consider the major physiological roles of P2X1-P2X7 and discuss whether enhancement of P2X receptor activity would offer any therapeutic benefit. We will review what is known about identified compounds acting as positive allosteric modulators and the recent identification of drug binding pockets for such modulators.
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Affiliation(s)
- Leanne Stokes
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Stefan Bidula
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Lučka Bibič
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Elizabeth Allum
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
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40
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Feng LL, Cai YQ, Zhu MC, Xing LJ, Wang X. The yin and yang functions of extracellular ATP and adenosine in tumor immunity. Cancer Cell Int 2020; 20:110. [PMID: 32280302 PMCID: PMC7137337 DOI: 10.1186/s12935-020-01195-x] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 03/27/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular adenosine triphosphate (eATP) and its main metabolite adenosine (ADO) constitute an intrinsic part of immunological network in tumor immunity. The concentrations of eATP and ADO in tumor microenvironment (TME) are controlled by ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed on immune cells, endothelial cells and cancer cells. Once accumulated in TME, eATP boosts antitumor immune responses, while ADO attenuates immunity against tumors. eATP and ADO, like yin and yang, represent two opposite aspects from immune-activating to immune-suppressive signals. Here we reviewed the functions of eATP and ADO in tumor immunity and attempt to block eATP hydrolysis, ADO formation and their contradictory effects in tumor models, allowing the induction of effective anti-tumor immune responses in TME. These attempts documented that therapeutic approaches targeting eATP/ADO metabolism and function may be effective methods in cancer therapy.
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Affiliation(s)
- Li-Li Feng
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China
| | - Yi-Qing Cai
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China
| | - Ming-Chen Zhu
- 5Department of Clinical Laboratory, Nanjing Medical University Cancer Hospital & Jiangsu Cancer Hospital, Nanjing, 210009 Jiangsu China
| | - Li-Jie Xing
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China
| | - Xin Wang
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China.,2School of Medicine, Shandong University, Jinan, 250012 Shandong China.,Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021 Shandong China.,National clinical research center for hematologic diseases, Jinan, 250021 Shandong China
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41
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Zhang WJ, Hu CG, Zhu ZM, Luo HL. Effect of P2X7 receptor on tumorigenesis and its pharmacological properties. Biomed Pharmacother 2020; 125:109844. [PMID: 32004973 DOI: 10.1016/j.biopha.2020.109844] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 12/27/2019] [Accepted: 01/13/2020] [Indexed: 12/20/2022] Open
Abstract
The occurrence and development of tumors is a multi-factor, multi-step, multi-gene pathological process, and its treatment has been the most difficult problem in the field of medicine today. Therefore, exploring the relevant factors involved in the pathogenesis of tumors, improving the diagnostic rate, treatment rate, and prognosis survival rate of tumors have become an urgent problem to be solved. A large number of studies have shown that the P2X7 receptor (P2X7R) and the tumor microenvironment play an important role in regulating the growth, apoptosis, migration and invasion of tumor cells. P2X7R is an ATP ligand-gated cationic channel receptor, which exists in most tissues of the human body. The main function of P2X7R is to regulate the relevant cells (such as macrophages, lymphocytes, and glial cells) to release damaging factors and induce apoptosis and cell death. In recent years, with continuous research and exploration of P2X7R, it has been found that P2X7R exists on the surface of most tumor cells and plays an important role in tumor pathogenesis. The activation of the P2X7R can open the ion channels on the tumor cell membrane (sodium ion, calcium ion influx and potassium ion outflow), trigger rearrangement of the cytoskeleton and changes in membrane fluidity, allow small molecule substances to enter the cell, activate enzymes and kinases in related signaling pathways in cells (such as PKA, PKC, ERK1/2, AKT, and JNK), thereby affecting the development of tumor cells, and can also indirectly affect the growth, apoptosis and migration of tumor cells through tumor microenvironment. At present, P2X7R has been widely recognized for its important role in tumorigenesis and development. In this paper, we give a comprehensive description of the structure and function of the P2X7R gene. We also clarified the concept of tumor microenvironment and its effect on tumors, discussed the relevant pathological mechanisms in the development of tumors, and revealed the intrinsic relationship between P2X7R and tumors. We explored the pharmacological properties of P2X7R antagonists or inhibitors in reducing its expression as targeted therapy for tumors.
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Affiliation(s)
- Wen-Jun Zhang
- The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province, 343000, China
| | - Ce-Gui Hu
- The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province, 343000, China
| | - Zheng-Ming Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province, 343000, China
| | - Hong-Liang Luo
- The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province, 343000, China.
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42
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Bibic L, Herzig V, King GF, Stokes L. Development of High-Throughput Fluorescent-Based Screens to Accelerate Discovery of P2X Inhibitors from Animal Venoms. JOURNAL OF NATURAL PRODUCTS 2019; 82:2559-2567. [PMID: 31532206 PMCID: PMC7123434 DOI: 10.1021/acs.jnatprod.9b00410] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Animal venoms can play an important role in drug discovery, as they are a rich source of evolutionarily tuned compounds that target a variety of ion channels and receptors. To date, there are six FDA-approved drugs derived from animal venoms, with recent work using high-throughput platforms providing a variety of new therapeutic candidates. However, high-throughput methods for screening animal venoms against purinoceptors, one of the oldest signaling receptor families, have not been reported. Here, we describe a variety of quantitative fluorescent-based high-throughput screening (HTS) cell-based assays for screening animal venoms against ligand-gated P2X receptors. A diverse selection of 180 venoms from arachnids, centipedes, hymenopterans, and cone snails were screened, analyzed, and validated, both analytically and pharmacologically. Using this approach, we performed screens against human P2X3, P2X4, and P2X7 using three different fluorescent-based dyes on stable cell lines and isolated the active venom components. Our HTS assays are performed in 96-well format and allow simultaneous screening of multiple venoms on multiple targets, improving testing characteristics while minimizing costs, specimen material, and testing time. Moreover, utilizing our assays and applying them to the other natural product libraries, rather than venoms, might yield other novel natural products that modulate P2X activity.
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Affiliation(s)
- Lucka Bibic
- School
of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, U.K.
| | - Volker Herzig
- Institute
for Molecular Bioscience, University of
Queensland, St Lucia, QLD 4072, Australia
| | - Glenn F. King
- Institute
for Molecular Bioscience, University of
Queensland, St Lucia, QLD 4072, Australia
| | - Leanne Stokes
- School
of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, U.K.
- E-mail:
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43
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Lee Y, Kim MT, Rhodes G, Sack K, Son SJ, Rich CB, Kolachalama VB, Gabel CV, Trinkaus-Randall V. Sustained Ca2+ mobilizations: A quantitative approach to predict their importance in cell-cell communication and wound healing. PLoS One 2019; 14:e0213422. [PMID: 31017899 PMCID: PMC6481807 DOI: 10.1371/journal.pone.0213422] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 04/11/2019] [Indexed: 01/12/2023] Open
Abstract
Epithelial wound healing requires the coordination of cells to migrate as a unit over the basement membrane after injury. To understand the process of this coordinated movement, it is critical to study the dynamics of cell-cell communication. We developed a method to characterize the injury-induced sustained Ca2+ mobilizations that travel between cells for periods of time up to several hours. These events of communication are concentrated along the wound edge and are reduced in cells further away from the wound. Our goal was to delineate the role and contribution of these sustained mobilizations and using MATLAB analyses, we determined the probability of cell-cell communication events in both in vitro models and ex vivo organ culture models. We demonstrated that the injury response was complex and represented the activation of a number of receptors. In addition, we found that pannexin channels mediated the cell-cell communication and motility. Furthermore, the sustained Ca2+ mobilizations are associated with changes in cell morphology and motility during wound healing. The results demonstrate that both purinoreceptors and pannexins regulate the sustained Ca2+ mobilization necessary for cell-cell communication in wound healing.
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Affiliation(s)
- Yoonjoo Lee
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Min Tae Kim
- Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Garrett Rhodes
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Kelsey Sack
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
| | - Sung Jun Son
- Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Celeste B. Rich
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Vijaya B. Kolachalama
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Christopher V. Gabel
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Vickery Trinkaus-Randall
- Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
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Abstract
Cancer metastasis is the second leading cause of death in the United States. Despite its morbidity, metastasis is an inefficient process that few cells can survive. However, cancer cells can overcome these metastatic barriers via cellular responses to microenvironmental cues, such as through mechanotransduction. This review focuses on the mechanosensitive ion channels TRPV4 and P2X7, and their roles in metastasis, as both channels have been shown to significantly affect tumor cell dissemination. Upon activation, these channels help form tumor neovasculature, promote transendothelial migration, and increase cell motility. Conversely, they have also been linked to forms of cancer cell death dependent upon levels of activation, implying the complex functionality of mechanosensitive ion channels. Understanding the roles of TRPV4, P2X7 and other mechanosensitive ion channels in these processes may reveal new possible drug targets that modify channel function to reduce a tumor's metastatic potential.
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45
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Zeng D, Yao P, Zhao H. P2X7, a critical regulator and potential target for bone and joint diseases. J Cell Physiol 2018; 234:2095-2103. [PMID: 30317598 DOI: 10.1002/jcp.27544] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 09/13/2018] [Indexed: 12/18/2022]
Abstract
Abundant evidence indicted that P2X7 receptor show a essential role in human health and some human diseases including hypertension, atherosclerosis, pulmonary inflammation, tuberculosis infection, psychiatric disorders, and cancer. P2X7 receptor also has an important role in some central nervous system diseases such as neurodegenerative disorders. Recently, more research suggested that P2X7 receptor also plays a crucial role in bone and joint diseases. But the effect of P2X7 receptor on skeletal and joint diseases has not been systematically reviewed. In this article, the role of P2X7 receptor in skeletal and joint diseases is elaborated. The activation of P2X7 receptor can ameliorate osteoporosis by inducing a fine balance between osteoclastic resorption and osteoblastic bone formation. The activation of P2X7 receptor can relieve the stress fracture injury by increasing the response to mechanical loading and inducing osteogenesis. But the activation of P2X7 receptor mediates the cell growth and cell proliferation in bone cancer. In addition, the activation of P2X7 receptor can aggravate the process of some joint diseases such as osteoarthritis, rheumatoid arthritis, and acute gouty arthritis. The inhibition of P2X7 receptor can alleviate the pathological process of joint disease to some extent. In conclusion, P2X7 receptor may be a critical regulator and therapeutic target for bone and joint diseases.
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Affiliation(s)
- Dehui Zeng
- Department of Orthopedics, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Pingbo Yao
- Department of Orthopedics, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Hong Zhao
- Institute of Pharmacy and Pharmacology, Nursing College, University of South China, Hengyang, China
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Di Virgilio F, Sarti AC, Falzoni S, De Marchi E, Adinolfi E. Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer 2018; 18:601-618. [PMID: 30006588 DOI: 10.1038/s41568-018-0037-0] [Citation(s) in RCA: 493] [Impact Index Per Article: 70.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Modulation of the biochemical composition of the tumour microenvironment is a new frontier of cancer therapy. Several immunosuppressive mechanisms operate in the milieu of most tumours, a condition that makes antitumour immunity ineffective. One of the most potent immunosuppressive factors is adenosine, which is generated in the tumour microenvironment owing to degradation of extracellular ATP. Accruing evidence over the past few years shows that ATP is one of the major biochemical constituents of the tumour microenvironment, where it acts at P2 purinergic receptors expressed on both tumour and host cells. Stimulation of P2 receptors has different effects depending on the extracellular ATP concentration, the P2 receptor subtype engaged and the target cell type. Among P2 receptors, the P2X purinergic receptor 7 (P2X7R) subtype appears to be a main player in host-tumour cell interactions. Preclinical studies in several tumour models have shown that P2X7R targeting is potentially a very effective anticancer treatment, and many pharmaceutical companies have now developed potent and selective small molecule inhibitors of P2X7R. In this Review, we report on the multiple mechanisms by which extracellular ATP shapes the tumour microenvironment and how its stimulation of host and tumour cell P2 receptors contributes to determining tumour fate.
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Affiliation(s)
- Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
| | - Alba Clara Sarti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Simonetta Falzoni
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Elena De Marchi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Elena Adinolfi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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47
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The P2X4 purinergic receptor regulates hepatic myofibroblast activation during liver fibrogenesis. J Hepatol 2018; 69:644-653. [PMID: 29802948 DOI: 10.1016/j.jhep.2018.05.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 04/07/2018] [Accepted: 05/14/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Liver fibrosis is characterized by the accumulation of extracellular matrix produced by hepatic myofibroblasts (hMF), the activation of which is critical to the fibrogenic process. Extracellular ATP, released by dying or stressed cells, and its purinergic receptors, constitute a powerful signaling network after injury. Although the purinergic receptor P2X4 (P2RX4) is highly expressed in the liver, its functions in hMF had never been investigated during liver fibrogenesis. METHODS In vivo, bile duct ligation was performed and methionine- and choline-deficient diet administered in wild-type and P2x4 knock-out (P2x4-KO) mice. In vitro, hMF were isolated from mouse (wild-type and P2x4-KO) and human liver. P2X4 pharmacological inhibition (in vitro and in vivo) and P2X4 siRNAs (in vitro) were used. Histological, biochemical and cell culture analysis allowed us to study P2X4 expression and its involvement in the regulation of fibrogenic and fibrolytic factors, as well as of hMF activation markers and properties. RESULTS P2X4 genetic invalidation or pharmacological inhibition protected mice from liver fibrosis and hMF accumulation after bile duct ligation or methionine- and choline-deficient diet. Human and mouse hMFs expressed P2X4, mainly in lysosomes. Invalidation of P2X4 in human and mouse hMFs blunted their activation marker expression and their fibrogenic properties. Finally, we showed that P2X4 regulates calcium entry and lysosomal exocytosis in hMF, impacting on ATP release, profibrogenic secretory profile, and transcription factor activation. CONCLUSION P2X4 expression and activation is critical for hMF to sustain their activated and fibrogenic phenotype. Therefore, the inactivation of P2X4 may be of therapeutic interest during liver fibrotic diseases. LAY SUMMARY During chronic injury, the liver often repairs with fibrotic tissue, which impairs liver function, and for which there is currently no treatment. We found that a previously unexplored pathway involving the purinergic receptor P2X4, can modulate fibrotic liver repair. Therefore, this receptor could be of interest in the development of novel therapies for fibrotic liver diseases.
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48
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Burnstock G, Knight GE. The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. Purinergic Signal 2018; 14:1-18. [PMID: 29164451 PMCID: PMC5842154 DOI: 10.1007/s11302-017-9593-0] [Citation(s) in RCA: 185] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/01/2017] [Indexed: 12/22/2022] Open
Abstract
Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK.
- Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Australia.
- Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia.
| | - Gillian E Knight
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK
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Ryu JW, Choe SS, Ryu SH, Park EY, Lee BW, Kim TK, Ha CH, Lee SW. Paradoxical induction of growth arrest and apoptosis by EGF via the up-regulation of PTEN by activating Redox factor-1/Egr-1 in human lung cancer cells. Oncotarget 2018; 8:4181-4195. [PMID: 27935858 PMCID: PMC5354822 DOI: 10.18632/oncotarget.13809] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 11/24/2016] [Indexed: 12/12/2022] Open
Abstract
Epidermal growth factor (EGF) signaling promotes cell proliferation and survival in several types of cancer. Here, however, we showed that EGF inhibits proliferation and promotes programmed cell death in non-small cell lung cancer (NSCLC) cells. In A549 cells, EGF increased redox factor-1 (Ref-1) expression and the association of Ref-1 with zinc finger-containing transcriptional regulator (EGR1) via activation of p22phox, RAC1, and an NADPH oxidase subunit. EGF increased p22phox and RAC1 expression through activation of purinergic receptors (P2Y). Elevated Ref-1/EGR1 levels increased phosphatase and tensin homolog (PTEN) levels, leading to inhibition of the Akt pathway. EGF-induced PTEN upregulation increased apoptosis and autophagy-induced damage in A549 cells, whereas Ref-1 knockdown blocked EGF-induced PTEN upregulation in an NADPH oxidase p22phox subunit-independent manner. In addition, p22phox knockdown restored EGF-induced effects, implying that changes in P2Y activity caused by EGF, which activates NADPH oxidase via RAC1, influenced Ref-1-mediated redox regulation. Finally, EGF similarly attenuated cell proliferation and promoted autophagy and apoptosis in vivo in a xenograft model using A549 cells. These findings reveal that EGF-induced redox signaling is linked to Ref-1-induced death in NSCLC cells.
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Affiliation(s)
- Je-Won Ryu
- Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung Sik Choe
- Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Institutive Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Republic of Korea
| | - Seung-Hee Ryu
- Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun-Young Park
- Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Byoung Wook Lee
- Asan Institute for Life Science, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Tae Keun Kim
- Department of Life Science, College of Natural Science, Hallym University, Kyeongki Province, Republic of Korea
| | - Chang Hoon Ha
- Asan Institute for Life Science, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang-Wook Lee
- Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea
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