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Téllez Garcia JM, Steenvoorden T, Bemelman F, Hilhorst M, Tammaro A, Vogt L. Purinoreceptor P2X7 in Extracellular ATP-Mediated Inflammation through the Spectrum of Kidney Diseases and Kidney Transplantation. J Am Soc Nephrol 2025:00001751-990000000-00602. [PMID: 40152923 DOI: 10.1681/asn.0000000711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/24/2025] [Indexed: 03/30/2025] Open
Abstract
Extracellular purines not only play a critical role in maintaining a balanced inflammatory response but may also trigger disproportionate inflammation in various kidney pathologies. Extracellular ATP is the most well-characterized inflammatory purine, which serves as a potent extracellular danger-associated molecular pattern ( i.e ., danger-associated molecular pattern). It signals through the P2 purinoreceptors during both acute and chronic kidney damage. The purinoreceptor P2X7 (P2X7R) has been extensively studied in kidney disease because of its potent ability to enhance inflammation by activating the nucleotide-binding oligomerization domain, leucine rich repeat family pyrin domain containing 3 inflammasome in both immune and parenchymal tubular cells and potential role in immunometabolic reprogramming. We will explore how, following a primary insult to the kidney, disturbance of purinergic balance characterized by extracellular ATP-mediated P2X7R activation exacerbates AKI. Second, we will describe how persistent purinergic disbalance promotes a P2X7R-mediated protracted inflammatory reaction leading to the progression of CKD of different etiologies. Finally, we will also highlight the relevant and emerging role of P2X7R signaling in both antigen-presenting cells and adaptive immune cells to modulate cellular and humoral immune responses in kidney transplantation and hypertension. This review underscores that ATP-P2X7R axis is a key driver of pathologic purinergic signaling, representing a largely unexplored but highly promising clinical target against a wide spectrum of kidney diseases.
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Affiliation(s)
- Juan Miguel Téllez Garcia
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, The Netherlands
| | - Thei Steenvoorden
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Frederike Bemelman
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Marc Hilhorst
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Alessandra Tammaro
- Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Pathology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Liffert Vogt
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
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2
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Chi ZC. Relationship between purinergic P2X7 receptor and colorectal cancer: Research progress and future prospect. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2025; 33:169-177. [DOI: https:/dx.doi.org/10.11569/wcjd.v33.i3.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
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Chi ZC. Relationship between purinergic P2X7 receptor and colorectal cancer: Research progress and future prospect. Shijie Huaren Xiaohua Zazhi 2025; 33:169-177. [DOI: 10.11569/wcjd.v33.i3.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/10/2025] [Accepted: 03/16/2025] [Indexed: 03/28/2025] Open
Abstract
Purinergic P2X7 receptor (P2X7R) is a cellular transmembrane protein. Its activation leads to the release of cytokines, causing the migration and invasion of cancer cells. The expression of P2X7R is associated with tumor inflammation, survival, proliferation, angiogenesis, and metastasis in colorectal cancer (CRC). Evidence suggests that P2X7R expression appears to be epigenetically regulated by DNA methylation and miRNA regulation. With the in-depth study of P2X7R, the application of P2X7R agonists and antagonists has been discussed in the treatment of CRC. This article reviews the relationship between P2X7R and CRC, focusing on the research progress and future prospects of P2X7R in CRC diagnosis and treat-ment.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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4
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Eghbalifard N, Nouri N, Rouzbahani S, Bakhshi M, Ghasemi Kahrizsangi N, Golafshan F, Abbasi F. Hypoxia signaling in cancer: HIF-1α stimulated by COVID-19 can lead to cancer progression and chemo-resistance in oral squamous cell carcinoma (OSCC). Discov Oncol 2025; 16:399. [PMID: 40138101 PMCID: PMC11947373 DOI: 10.1007/s12672-025-02150-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
The potential implications of Coronavirus disease-2019 (COVID-19) on oral squamous cell carcinoma (OSCC) development, chemo-resistance, tumor recurrence, and patient outcomes are explored, emphasizing the urgent need for tailored therapeutic strategies to mitigate these risks. The role of hypoxia-inducible factor 1-alpha (HIF-1α) in OSCC studies has highlighted HIF-1α as a crucial prognostic marker in OSCC, with implications for disease prognosis and patient survival. Its overexpression has been linked to aggressive subtypes in early OSCC stages, indicating its significance as an early biomarker for disease progression. Moreover, dysplastic lesions with heightened HIF-1α expression exhibit a greater propensity for malignant transformation, underscoring its role in early oral carcinogenesis. Cancer patients, including those with OSCC, face an elevated risk of severe COVID-19 complications, which may further impact cancer progression and treatment outcomes. Understanding the interplay between COVID-19 infection, HIF-1α activation, and OSCC pathogenesis is crucial for enhancing clinical management strategies. So, insights from this review shed light on the significance of HIF-1α in OSCC tumorigenesis, metastasis formation, and patient prognosis. The review underscores the need for further research to elucidate the precise mechanisms through which HIF-1α modulates cancer progression and chemo-resistance in the context of COVID-19 infection. Such knowledge is essential for developing targeted therapeutic interventions to improve outcomes for OSCC patients.
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Affiliation(s)
- Negar Eghbalifard
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nikta Nouri
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shiva Rouzbahani
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Bakhshi
- Islamic Azad University of Najaf Abad, Affiliated Hospitals, Isfahan, Iran
| | - Negin Ghasemi Kahrizsangi
- Child Growth and Development Research Center, Research Institute for Primary Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Faraz Golafshan
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Abbasi
- Department of Obstetrics and Gynecology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
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Li Y, Zhang X, Wang J, Wang K, Li B, Qiao X, He W, Cai J, Liu D, Yang LL. Leveraging adenosine triphosphate for cancer theranostics. Theranostics 2025; 15:4708-4733. [PMID: 40225571 PMCID: PMC11984400 DOI: 10.7150/thno.106291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 02/20/2025] [Indexed: 04/15/2025] Open
Abstract
Manipulation of the biochemical composition of the tumor microenvironment (TME) is a thriving research area in cancer treatment. Adenosine triphosphate (ATP), a key biochemical component, serves as an energy source for cancer cell proliferation. Notably, ATP can also act as a potent signal transducer to prime anti-tumor immune responses. There is increasing attention given to both the tumor-promoting and tumor-inhibiting roles of ATP in the context of possible new treatments for cancer. ATP levels in the TME are known to be significantly greater than in non-tumor tissues. This disparity presents an opportunity to exploit the ATP response for the delivery of anti-tumor drugs and tumor diagnosis. In this article, we provide a comprehensive overview of the existing strategies and mechanisms for ATP-based therapy and cancer diagnosis. We also discuss the current challenges in the field and propose potential areas for future research, to provide researchers with insights to further investigate the potential of ATP in cancer theranostics.
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Affiliation(s)
| | | | | | | | | | | | | | - Jinghua Cai
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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Santana PT, de Lima IS, da Silva e Souza KC, Barbosa PHS, de Souza HSP. Persistent Activation of the P2X7 Receptor Underlies Chronic Inflammation and Carcinogenic Changes in the Intestine. Int J Mol Sci 2024; 25:10874. [PMID: 39456655 PMCID: PMC11507540 DOI: 10.3390/ijms252010874] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/06/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Aberrant signaling through damage-associated molecular patterns (DAMPs) has been linked to several health disorders, attracting considerable research interest over the last decade. Adenosine triphosphate (ATP), a key extracellular DAMP, activates the purinergic receptor P2X7, which acts as a danger sensor in immune cells and is implicated in distinct biological functions, including cell death, production of pro-inflammatory cytokines, and defense against microorganisms. In addition to driving inflammation mediated by immune and non-immune cells, the persistent release of endogenous DAMPs, including ATP, has been shown to result in epigenetic modifications. In intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), consequent amplification of the inflammatory response and the resulting epigenetic reprogramming may impact the development of pathological changes associated with specific disease phenotypes. P2X7 is overexpressed in the gut mucosa of patients with IBD, whereas the P2X7 blockade prevents the development of chemically induced experimental colitis. Recent data suggest a role for P2X7 in determining gut microbiota composition. Regulatory mechanisms downstream of the P2X7 receptor, combined with signals from dysbiotic microbiota, trigger intracellular signaling pathways and inflammasomes, intensify inflammation, and foster colitis-associated CRC development. Preliminary studies targeting the ATP-P2X7 pathway have shown favorable therapeutic effects in human IBD and experimental colitis.
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Affiliation(s)
- Patricia Teixeira Santana
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (P.T.S.); (I.S.d.L.); (K.C.d.S.e.S.); (P.H.S.B.)
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro 22281-100, Brazil
| | - Isadora Schmukler de Lima
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (P.T.S.); (I.S.d.L.); (K.C.d.S.e.S.); (P.H.S.B.)
| | - Karen Cristina da Silva e Souza
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (P.T.S.); (I.S.d.L.); (K.C.d.S.e.S.); (P.H.S.B.)
| | - Pedro Henrique Sales Barbosa
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (P.T.S.); (I.S.d.L.); (K.C.d.S.e.S.); (P.H.S.B.)
| | - Heitor Siffert Pereira de Souza
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (P.T.S.); (I.S.d.L.); (K.C.d.S.e.S.); (P.H.S.B.)
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro 22281-100, Brazil
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Yang JK, Kim J, Ahn YH, Bae SH, Baek MJ, Lee SH, Moon JS. Inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human hepatocellular carcinoma. BMB Rep 2024; 57:459-464. [PMID: 39219047 PMCID: PMC11524825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/07/2024] [Accepted: 09/01/2024] [Indexed: 09/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. HCC occurs people with chronic liver diseases. The purinergic receptor P2X 7 (P2RX7) is involved in tumor proliferation and growth. Also, P2RX7 is associated with tumor invasion and metastatic dissemination. High glucose utilization is important for the survival of various types of tumors. However, the role of P2RX7 in glucose metabolism and cellular survival of HCC remains unclear. Here, our results show that the gene and protein levels of P2RX7 were elevated in tumor cells of patients with HCC. The pharmacological inhibition of P2RX7 by A-804598, a selective P2RX7 antagonist, and genetic inhibition by P2RX7 knockdown suppressed the glycolytic activity by reduction of hexokinase 2 (HK2), a key enzyme of the glycolysis pathway, in human HCC cells. Also, both A-804598 treatment and P2RX7 knockdown induced cytotoxicity via inhibition of AKT activation which is critical for tumor cell survival in human HCC cells. Moreover, A-804598 treatment and P2RX7 knockdown increased cytotoxicity and caspase-3 activation in human HCC cells. These results suggest that inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human HCC. [BMB Reports 2024; 57(10): 459-464].
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Affiliation(s)
- Jae Kook Yang
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Junhyung Kim
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Korea
| | - Young Hyeon Ahn
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Sang Ho Bae
- Department of Surgery, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Moo-Jun Baek
- Department of Surgery, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Jong-Seok Moon
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Korea
- Department of Pathology, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
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8
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Logan IE, Nguyen KT, Chatterjee T, Manivannan B, Paul NP, Kim SR, Sixta EM, Bastian LP, Marean-Reardon C, Karajannis MA, Fernández-Valle C, Estevez AG, Franco MC. Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation. Redox Biol 2024; 75:103249. [PMID: 38945076 PMCID: PMC11261529 DOI: 10.1016/j.redox.2024.103249] [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: 05/21/2024] [Revised: 06/10/2024] [Accepted: 06/18/2024] [Indexed: 07/02/2024] Open
Abstract
Tumors develop in an oxidative environment characterized by peroxynitrite production and downstream protein tyrosine (Y) nitration. We showed that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inheritable tumor disorder NF2-related Schwannomatosis (NF2-SWN). Here, we identified the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation. Doubling the endogenous levels of nitrated Hsp90 in schwannoma cells or supplementing nitrated Hsp90 into normal Schwann cells increased their proliferation. Metabolically, nitration on either Y33 or Y56 conferred Hsp90 distinct functions; nitration at Y33 (Hsp90NY33) down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 (Hsp90NY56) increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90NY33 and Hsp90NY56 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. Collectively, these results underscore the role of tyrosine nitration as a post-translational modification regulating critical cellular processes. Nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets.
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Affiliation(s)
- Isabelle E Logan
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA; Center for Translational Science, Florida International University, Florida, 34987, USA
| | - Kyle T Nguyen
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
| | - Tilottama Chatterjee
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
| | | | - Ngozi P Paul
- Center for Translational Science, Florida International University, Florida, 34987, USA
| | - Sharon R Kim
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
| | - Evelyn M Sixta
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
| | - Lydia P Bastian
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
| | - Carrie Marean-Reardon
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
| | - Matthias A Karajannis
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Cristina Fernández-Valle
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
| | - Alvaro G Estevez
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA; Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Florida, 33199, USA
| | - Maria Clara Franco
- Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA; Center for Translational Science, Florida International University, Florida, 34987, USA; Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Florida, 33199, USA.
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Nuñez-Ríos JD, Reyna-Jeldes M, Mata-Martínez E, Campos-Contreras ADR, Lazcano-Sánchez I, González-Gallardo A, Díaz-Muñoz M, Coddou C, Vázquez-Cuevas FG. Extracellular ATP/P2X7 receptor, a regulatory axis of migration in ovarian carcinoma-derived cells. PLoS One 2024; 19:e0304062. [PMID: 38870128 PMCID: PMC11175443 DOI: 10.1371/journal.pone.0304062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/06/2024] [Indexed: 06/15/2024] Open
Abstract
ATP is actively maintained at high concentrations in cancerous tissues, where it promotes a malignant phenotype through P2 receptors. In this study, we first evaluated the effect of extracellular ATP depletion with apyrase in SKOV-3, a cell line derived from metastatic ovarian carcinoma. We observed a decrease in cell migration and an increase in transepithelial electrical resistance and cell markers, suggesting a role in maintaining a mesenchymal phenotype. To identify the P2 receptor that mediated the effects of ATP, we compared the transcript levels of some P2 receptors and found that P2RX7 is three-fold higher in SKOV-3 cells than in a healthy cell line, namely HOSE6-3 (from human ovarian surface epithelium). Through bioinformatic analysis, we identified a higher expression of the P2RX7 transcript in metastatic tissues than in primary tumors; thus, P2X7 seems to be a promising effector for the malignant phenotype. Subsequently, we demonstrated the presence and functionality of the P2X7 receptor in SKOV-3 cells and showed through pharmacological approaches that its activity promotes cell migration and contributes to maintaining a mesenchymal phenotype. P2X7 activation using BzATP increased cell migration and abolished E-cadherin expression. On the other hand, a series of P2X7 receptor antagonists (A438079, BBG and OxATP) decreased cell migration. We used a CRISPR-based knock-out system directed to P2RX7. According to the results of our wound-healing assay, SKOV3-P2X7KO cells lacked receptor-mediated calcium mobilization and decreased migration. Altogether, these data let us propose that P2X7 receptor is a regulator for cancer cell migration and thus a potential drug target.
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Affiliation(s)
- José David Nuñez-Ríos
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Mauricio 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, Coquimbo, Chile
| | - Esperanza Mata-Martínez
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Anaí del Rocío Campos-Contreras
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Iván Lazcano-Sánchez
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Adriana González-Gallardo
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - Claudio 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, Coquimbo, Chile
| | - Francisco G. Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
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Longo Y, Mascaraque SM, Andreacchio G, Werner J, Katahira I, De Marchi E, Pegoraro A, Lebbink RJ, Köhrer K, Petzsch P, Tao R, Di Virgilio F, Adinolfi E, Drexler I. The purinergic receptor P2X7 as a modulator of viral vector-mediated antigen cross-presentation. Front Immunol 2024; 15:1360140. [PMID: 38711513 PMCID: PMC11070468 DOI: 10.3389/fimmu.2024.1360140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 04/05/2024] [Indexed: 05/08/2024] Open
Abstract
Introduction Modified Vaccinia Virus Ankara (MVA) is a safe vaccine vector inducing long- lasting and potent immune responses. MVA-mediated CD8+T cell responses are optimally induced, if both, direct- and cross-presentation of viral or recombinant antigens by dendritic cells are contributing. Methods To improve the adaptive immune responses, we investigated the role of the purinergic receptor P2X7 (P2RX7) in MVA-infected feeder cells as a modulator of cross-presentation by non-infected dendritic cells. The infected feeder cells serve as source of antigen and provide signals that help to attract dendritic cells for antigen take up and to license these cells for cross-presentation. Results We demonstrate that presence of an active P2RX7 in major histocompatibility complex (MHC) class I (MHCI) mismatched feeder cells significantly enhanced MVA-mediated antigen cross-presentation. This was partly regulated by P2RX7-specific processes, such as the increased availability of extracellular particles as well as the altered cellular energy metabolism by mitochondria in the feeder cells. Furthermore, functional P2RX7 in feeder cells resulted in a delayed but also prolonged antigen expression after infection. Discussion We conclude that a combination of the above mentioned P2RX7-depending processes leads to significantly increased T cell activation via cross- presentation of MVA-derived antigens. To this day, P2RX7 has been mostly investigated in regards to neuroinflammatory diseases and cancer progression. However, we report for the first time the crucial role of P2RX7 for antigen- specific T cell immunity in a viral infection model.
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Affiliation(s)
- Ylenia Longo
- Institute of Virology, Universitätsklinikum Düsseldorf, Düsselorf, Germany
| | | | | | - Julia Werner
- Institute of Molecular Medicine II, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Ichiro Katahira
- Institute of Molecular Medicine II, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Elena De Marchi
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Anna Pegoraro
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Robert Jan Lebbink
- Institute of Infection Immunity, University of Utrecht, Utrecht, Netherlands
| | - Karl Köhrer
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Patrick Petzsch
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ronny Tao
- Institute of Virology, Universitätsklinikum Düsseldorf, Düsselorf, Germany
| | | | - Elena Adinolfi
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Ingo Drexler
- Institute of Virology, Universitätsklinikum Düsseldorf, Düsselorf, Germany
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11
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Grassi F, Marino R. The P2X7 receptor in mucosal adaptive immunity. Purinergic Signal 2024; 20:9-19. [PMID: 37067746 PMCID: PMC10828151 DOI: 10.1007/s11302-023-09939-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/31/2023] [Indexed: 04/18/2023] Open
Abstract
The P2X7 receptor (P2X7R) is a widely distributed cation channel activated by extracellular ATP (eATP) with exclusive peculiarities with respect to other P2XRs. In recent years, P2X7R has been shown to regulate the adaptive immune response by conditioning T cell signaling and activation as well as polarization, lineage stability, cell death, and function in tissues. Here we revise experimental observations in this field, with a focus on adaptive immunity at mucosal sites, particularly in the gut, where eATP is hypothesized to act in the reciprocal conditioning of the host immune system and commensal microbiota to promote mutualism. The importance of P2X7R activity in the intestine is consistent with the transcriptional upregulation of P2xr7 gene by retinoic acid, a metabolite playing a key role in mucosal immunity. We emphasize the function of the eATP/P2X7R axis in controlling T follicular helper (Tfh) cell in the gut-associated lymphoid tissue (GALT) and, consequently, T-dependent secretory IgA (SIgA), with a focus on high-affinity SIgA-mediated protection from enteropathogens and shaping of a beneficial microbiota for the host.
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Affiliation(s)
- Fabio Grassi
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università Della Svizzera Italiana, 6500, Bellinzona, Switzerland.
| | - Rebecca Marino
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università Della Svizzera Italiana, 6500, Bellinzona, Switzerland
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12
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Zuo C, Xu YS, He PF, Zhang WJ. ATP ion channel P2X7 receptor as a regulatory molecule in the progression of colorectal cancer. Eur J Med Chem 2023; 261:115877. [PMID: 37857146 DOI: 10.1016/j.ejmech.2023.115877] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/12/2023] [Accepted: 10/12/2023] [Indexed: 10/21/2023]
Abstract
Large amounts of adenosine triphosphate (ATP), a natural P2X7 receptor activator, are released during colorectal carcinogenesis. P2X7 receptor activation regulates the activity of colorectal cancer (CRC) cells by mediating intracellular signal transduction. Importantly, the opening and activation of membrane pores of P2X7 receptor are different, which can play a dual role in promoting or inhibiting the progression of CRC. These can also depend on P2X7 receptor to regulate the activities of immune cells in the microenvironment, play the functions of immune regulation, immune escape and immune monitoring. While the use of P2X7 receptor antagonists (such as BBG, A438079 and A740003) can play a certain inhibitory pharmacological role on the activity of CRC. Therefore, in this paper, the mechanism and immunomodulatory function of P2X7 receptor involved in the progression of CRC were discussed. Moreover, we discussed the effect of antagonizing the activity of P2X7 receptor on the progression of CRC. So P2X7 receptor may be a new pharmacological molecular target for the treatment of CRC.
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Affiliation(s)
- Cheng Zuo
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi province, 343000, China
| | - Yong-Sheng Xu
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi province, 343000, China
| | - Peng-Fei He
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi province, 343000, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi province, 343000, China.
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13
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Zanoni M, Borges da Silva H, Adinolfi E. Editorial: Therapy resistance in tumor microenvironment: metabolic reprogramming and purinergic signaling. Front Oncol 2023; 13:1297152. [PMID: 38023158 PMCID: PMC10662014 DOI: 10.3389/fonc.2023.1297152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Affiliation(s)
- Michele Zanoni
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | | | - Elena Adinolfi
- Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Ferrara, Italy
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14
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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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15
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Adinolfi E, De Marchi E, Grignolo M, Szymczak B, Pegoraro A. The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk. Int J Mol Sci 2023; 24:13906. [PMID: 37762206 PMCID: PMC10531279 DOI: 10.3390/ijms241813906] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
The tumor niche is an environment rich in extracellular ATP (eATP) where purinergic receptors have essential roles in different cell subtypes, including cancer, immune, and stromal cells. Here, we give an overview of recent discoveries regarding the role of probably the best-characterized purinergic receptor in the tumor microenvironment: P2X7. We cover the activities of the P2X7 receptor and its human splice variants in solid and liquid cancer proliferation, dissemination, and crosstalk with immune and endothelial cells. Particular attention is paid to the P2X7-dependent release of microvesicles and exosomes, their content, including ATP and miRNAs, and, in general, P2X7-activated mechanisms favoring metastatic spread and niche conditioning. Moreover, the emerging role of P2X7 in influencing the adenosinergic axis, formed by the ectonucleotidases CD39 and CD73 and the adenosine receptor A2A in cancer, is analyzed. Finally, we cover how antitumor therapy responses can be influenced by or can change P2X7 expression and function. This converging evidence suggests that P2X7 is an attractive therapeutic target for oncological conditions.
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Affiliation(s)
- Elena Adinolfi
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (E.D.M.); (M.G.); (A.P.)
| | - Elena De Marchi
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (E.D.M.); (M.G.); (A.P.)
| | - Marianna Grignolo
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (E.D.M.); (M.G.); (A.P.)
| | - Bartosz Szymczak
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland;
| | - Anna Pegoraro
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (E.D.M.); (M.G.); (A.P.)
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16
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Kan LK, Drill M, Jayakrishnan PC, Sequeira RP, Galea E, Todaro M, Sanfilippo PG, Hunn M, Williams DA, O'Brien TJ, Drummond KJ, Monif M. P2X7 receptor antagonism by AZ10606120 significantly reduced in vitro tumour growth in human glioblastoma. Sci Rep 2023; 13:8435. [PMID: 37225786 DOI: 10.1038/s41598-023-35712-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 05/22/2023] [Indexed: 05/26/2023] Open
Abstract
Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14-18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.
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Affiliation(s)
- Liyen K Kan
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Matthew Drill
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | | | - Richard P Sequeira
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Emily Galea
- Department of Neurosurgery, The Alfred, Melbourne, VIC, Australia
| | - Marian Todaro
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia
- Department of Neurology, The Alfred, Melbourne, VIC, Australia
| | - Paul G Sanfilippo
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Martin Hunn
- Department of Neurosurgery, The Alfred, Melbourne, VIC, Australia
| | - David A Williams
- Department of Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia
- Department of Neurology, The Alfred, Melbourne, VIC, Australia
| | - Katharine J Drummond
- Department of Neurosurgery, The Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Mastura Monif
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
- Department of Physiology, The University of Melbourne, Melbourne, VIC, Australia.
- Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
- Department of Neurology, The Alfred, Melbourne, VIC, Australia.
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17
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Dou X, Chen R, Yang J, Dai M, Long J, Sun S, Lin Y. The potential role of T-cell metabolism-related molecules in chronic neuropathic pain after nerve injury: a narrative review. Front Immunol 2023; 14:1107298. [PMID: 37266437 PMCID: PMC10229812 DOI: 10.3389/fimmu.2023.1107298] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 04/27/2023] [Indexed: 06/03/2023] Open
Abstract
Neuropathic pain is a common type of chronic pain, primarily caused by peripheral nerve injury. Different T-cell subtypes play various roles in neuropathic pain caused by peripheral nerve damage. Peripheral nerve damage can lead to co-infiltration of neurons and other inflammatory cells, thereby altering the cellular microenvironment and affecting cellular metabolism. By elaborating on the above, we first relate chronic pain to T-cell energy metabolism. Then we summarize the molecules that have affected T-cell energy metabolism in the past five years and divide them into two categories. The first category could play a role in neuropathic pain, and we explain their roles in T-cell function and chronic pain, respectively. The second category has not yet been involved in neuropathic pain, and we focus on how they affect T-cell function by influencing T-cell metabolism. By discussing the above content, this review provides a reference for studying the direct relationship between chronic pain and T-cell metabolism and searching for potential therapeutic targets for the treatment of chronic pain on the level of T-cell energy metabolism.
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Affiliation(s)
- Xiaoke Dou
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juexi Yang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Maosha Dai
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junhao Long
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shujun Sun
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pain, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Lin
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Ledderose S, Rodler S, Eismann L, Ledderose G, Rudelius M, Junger WG, Ledderose C. P2X1 and P2X7 Receptor Overexpression Is a Negative Predictor of Survival in Muscle-Invasive Bladder Cancer. Cancers (Basel) 2023; 15:2321. [PMID: 37190249 PMCID: PMC10136747 DOI: 10.3390/cancers15082321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/10/2023] [Accepted: 04/14/2023] [Indexed: 05/17/2023] Open
Abstract
Bladder cancer is amongst the most common causes of cancer death worldwide. Muscle-invasive bladder cancer (MIBC) bears a particularly poor prognosis. Overexpression of purinergic P2X receptors (P2XRs) has been associated with worse outcome in several malignant tumors. Here, we investigated the role of P2XRs in bladder cancer cell proliferation in vitro and the prognostic value of P2XR expression in MIBC patients. Cell culture experiments with T24, RT4, and non-transformed TRT-HU-1 cells revealed a link between high ATP concentrations in the cell culture supernatants of bladder cell lines and a higher grade of malignancy. Furthermore, proliferation of highly malignant T24 bladder cancer cells depended on autocrine signaling through P2X receptors. P2X1R, P2X4R, and P2X7R expression was immunohistochemically analyzed in tumor specimens from 173 patients with MIBC. High P2X1R expression was associated with pathological parameters of disease progression and reduced survival time. High combined expression of P2X1R and P2X7R increased the risk of distant metastasis and was an independent negative predictor of overall and tumor-specific survival in multivariate analyses. Our results suggest that P2X1R/P2X7R expression scores are powerful negative prognostic markers in MIBC patients and that P2XR-mediated pathways are potential targets for novel therapeutic strategies in bladder cancer.
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Affiliation(s)
- Stephan Ledderose
- Institute of Pathology, Ludwig Maximilian University, 80337 Munich, Germany
| | - Severin Rodler
- Department of Urology, Ludwig Maximilian University, 81377 Munich, Germany
| | - Lennert Eismann
- Department of Urology, Ludwig Maximilian University, 81377 Munich, Germany
| | - Georg Ledderose
- Department of Oto-Rhino-Laryngology, Ludwig Maximilian University, 81377 Munich, Germany
| | - Martina Rudelius
- Institute of Pathology, Ludwig Maximilian University, 80337 Munich, Germany
| | - Wolfgang G. Junger
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Department of Surgery, University of California San Diego Health, La Jolla, CA 92037, USA
| | - Carola Ledderose
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Department of Surgery, University of California San Diego Health, La Jolla, CA 92037, USA
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19
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Santiago-Carvalho I, Banuelos A, Borges da Silva H. Tissue- and temporal-specific roles of extracellular ATP on T cell metabolism and function. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e00025. [PMID: 37143525 PMCID: PMC10150631 DOI: 10.1097/in9.0000000000000025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 04/13/2023] [Indexed: 05/06/2023]
Abstract
The activation and function of T cells is fundamental for the control of infectious diseases and cancer, and conversely can mediate several autoimmune diseases. Among the signaling pathways leading to T cell activation and function, the sensing of extracellular adenosine triphosphate (eATP) has been recently appreciated as an important component. Through a plethora of purinergic receptors, most prominently P2RX7, eATP sensing can induce a wide variety of processes in T cells, such as proliferation, subset differentiation, survival, or cell death. The downstream roles of eATP sensing can vary according to (a) the T cell subset, (b) the tissue where T cells are, and (c) the time after antigen exposure. In this mini-review, we revisit the recent findings on how eATP signaling pathways regulate T-cell immune responses and posit important unanswered questions on this field.
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Affiliation(s)
| | - Alma Banuelos
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA
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20
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de Salles ÉM, Raeder PL, Angeli CB, Santiago VF, de Souza CN, Ramalho T, Câmara NOS, Palmisano G, Álvarez JM, D'Império Lima MR. P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis. Front Immunol 2023; 14:1140426. [PMID: 36993971 PMCID: PMC10040773 DOI: 10.3389/fimmu.2023.1140426] [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: 01/09/2023] [Accepted: 02/24/2023] [Indexed: 03/16/2023] Open
Abstract
Introduction This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP). Methods In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation. Results We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. Conclusion These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.
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Affiliation(s)
- Érika Machado de Salles
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Paulo Lisboa Raeder
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Claudia Blanes Angeli
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Verônica Feijoli Santiago
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Cristiane Naffah de Souza
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Theresa Ramalho
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Niels Olsen Saraiva Câmara
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Giuseppe Palmisano
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - José Maria Álvarez
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
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21
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Wang Z, Zhu S, Tan S, Zeng Y, Zeng H. The P2 purinoceptors in prostate cancer. Purinergic Signal 2023; 19:255-263. [PMID: 35771310 PMCID: PMC9984634 DOI: 10.1007/s11302-022-09874-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/25/2022] [Indexed: 02/08/2023] Open
Abstract
P2 purinoceptors are composed of ligand-gated ion channel type (P2X receptor) and G protein-coupled metabolite type (P2Y receptor). Both these receptors have played important roles in the prostate cancer microenvironment in recent years. P2X and P2Y receptors can contribute to prostate cancer's growth and invasiveness. However, the comprehensive mechanisms have yet to be identified. By summarizing the relevant studies, we believe that P2X and P2Y receptors play a dual role in cancer cell growth depending on the prostate cancer microenvironment and different downstream signalling pathways. We also summarized how different signalling pathways contribute to tumor invasiveness and metastasis through P2X and P2Y receptors, focusing on understanding the specific mechanisms led by P2X4, P2X7, and P2Y2. Statins may reduce and prevent tumor progression through P2X7 so that P2X purinergic receptors may have clinical implications in the management of prostate cancer. Furthermore, P2X7 receptors can aid in the early detection of prostate cancer. We hope that this review will provide new insights for future mechanistic and clinical investigations into the role of P2 purinergic receptors in prostate cancer.
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Affiliation(s)
- Zilin Wang
- The Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Sha Zhu
- The Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Sirui Tan
- Department of Abdominal Cancer, Medical School, West China Hospital, Sichuan University, Cancer Center, Chengdu, West China, China
| | - Yuhao Zeng
- The Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Zeng
- The Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
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22
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Sheng G, Gao Y, Ding Q, Zhang R, Wang T, Jing S, Zhao H, Ma T, Wu H, Yang Y. P2RX7 promotes osteosarcoma progression and glucose metabolism by enhancing c-Myc stabilization. J Transl Med 2023; 21:132. [PMID: 36803784 PMCID: PMC9940387 DOI: 10.1186/s12967-023-03985-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/13/2023] [Indexed: 02/22/2023] Open
Abstract
BACKGROUND Osteosarcoma is the most common malignant tumor in bone and its prognosis has reached a plateau in the past few decades. Recently, metabolic reprogramming has attracted increasing attention in the field of cancer research. In our previous study, P2RX7 has been identified as an oncogene in osteosarcoma. However, whether and how P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming remains unexplored. METHODS We used CRISPR/Cas9 genome editing technology to establish P2RX7 knockout cell lines. Transcriptomics and metabolomics were performed to explore metabolic reprogramming in osteosarcoma. RT-PCR, western blot and immunofluorescence analyses were used to determine gene expression related to glucose metabolism. Cell cycle and apoptosis were examined by flowcytometry. The capacity of glycolysis and oxidative phosphorylation were assessed by seahorse experiments. PET/CT was carried out to assess glucose uptake in vivo. RESULTS We demonstrated that P2RX7 significantly promotes glucose metabolism in osteosarcoma via upregulating the expression of genes related to glucose metabolism. Inhibition of glucose metabolism largely abolishes the ability of P2RX7 to promote osteosarcoma progression. Mechanistically, P2RX7 enhances c-Myc stabilization by facilitating nuclear retention and reducing ubiquitination-dependent degradation. Furthermore, P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming in a predominantly c-Myc-dependent manner. CONCLUSIONS P2RX7 plays a key role in metabolic reprogramming and osteosarcoma progression via increasing c-Myc stability. These findings provide new evidence that P2RX7 might be a potential diagnostic and/or therapeutic target for osteosarcoma. Novel therapeutic strategies targeting metabolic reprogramming appear to hold promise for a breakthrough in the treatment of osteosarcoma.
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Affiliation(s)
- Gaohong Sheng
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Yuan Gao
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qing Ding
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Ruizhuo Zhang
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Tianqi Wang
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Shaoze Jing
- grid.470966.aShanxi Bethune Hospital, Tongji Shanxi Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032 China
| | - Hongqi Zhao
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Tian Ma
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China.
| | - Yong Yang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China.
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von Mücke-Heim IA, Deussing JM. The P2X7 receptor in mood disorders: Emerging target in immunopsychiatry, from bench to bedside. Neuropharmacology 2023; 224:109366. [PMID: 36470368 DOI: 10.1016/j.neuropharm.2022.109366] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/09/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
Psychiatric disorders are among the most burdensome disorders worldwide. Though therapies have evolved over the last decades, treatment resistance still affects many patients. Recently, neuroimmune systems have been identified as important factors of mood disorder biology. The underlying dysregulation in neuroimmune cross-talk is driven by genetic risk factors and accumulating adverse environmental influences like chronic psychosocial stress. These result in a cluster of proinflammatory cytokines and quantitative and functional changes of immune cell populations (e.g., microglia, monocytes, T cells), varying by disease entity and state. Among the emerging immune targets, purinergic signalling revolving around the membranous and ATP specific P2X7 receptor (P2X7R) has gained wider attention and clinical studies making use of antagonistic drugs are on-going. Still, no clinically meaningful applications have been identified so far. A major problem is the often overly simplified approach taken to translate findings from bench to bedside. Therefore, the present review focuses on purinergic signalling via P2X7R in the context of recent advances in immunopsychiatric mood disorder research. Our aim is to provide an overview of the current P2X7R-related findings, from bench to bedside. First, we summarize the characteristics of purinergic signalling and P2X7R, followed by a depiction of genetic and clinical data connecting P2X7R to mood disorders. We close with our perspective on current developments and discuss changes necessary to translate the evident potential of P2X7R signalling modulation into meaningful clinical application. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.
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Affiliation(s)
| | - Jan M Deussing
- Max Planck Institute for Psychiatry, Molecular Neurogenetics, Munich, Germany.
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24
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Bai X, Li X, Qiao C, Tang Y, Zhao R, Peng X. Progress in the relationship between P2X7R and colorectal cancer. Mol Biol Rep 2023; 50:1687-1699. [PMID: 36417079 DOI: 10.1007/s11033-022-07939-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 09/08/2022] [Indexed: 11/24/2022]
Abstract
Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a nonselective cation channel of the purinergic receptor family. P2X7R is activated by adenosine triphosphate (ATP) and plays a significant role in inflammatory and autoimmune diseases by triggering cellular signal transduction. More importantly, P2X7R is abnormally expressed in many tumor cells and is involved in the progression of various tumor cells. Studies have shown that the irregular expression of P2X7R in colorectal cancer (CRC) can not only indirectly affect the occurrence and development of CRC by promoting inflammatory bowel disease but also directly affect the proliferation and metastasis of CRC cells. P2X7R plays a bidirectional role in cancer induction and inhibition by mediating complex signaling pathways in CRC, and its expression level is closely related to the overall survival of CRC patients. Therefore, P2X7R may be a biomarker and potential therapeutic target for the development and prognosis of CRC. In this paper, we review the research progress on P2X7R in CRC.
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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
| | - 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.
| | - 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
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25
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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: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [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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26
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Hatami H, Sajedi A, Mir SM, Memar MY. Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells. Health Sci Rep 2023; 6:e996. [PMID: 36570342 PMCID: PMC9768844 DOI: 10.1002/hsr2.996] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 11/28/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022] Open
Abstract
Background In most regions, cancer ranks the second most frequent cause of death following cardiovascular disorders. Aim In this article, we review the various aspects of glycolysis with a focus on types of MCTs and the importance of lactate in cancer cells. Results and Discussion Metabolic changes are one of the first and most important alterations in cancer cells. Cancer cells use different pathways to survive, energy generation, growth, and proliferation compared to normal cells. The increase in glycolysis, which produces substances such as lactate and pyruvate, has an important role in metastases and invasion of cancer cells. Two important cellular proteins that play a role in the production and transport of lactate include lactate dehydrogenase and monocarboxylate transporters (MCTs). These molecules by their various isoforms and different tissue distribution help to escape the immune system and expansion of cancer cells under different conditions.
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Affiliation(s)
- Hamed Hatami
- Department of Immunology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Atefe Sajedi
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
| | - Seyed Mostafa Mir
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Clinical Biochemistry, Faculty of MedicineGolestan University of Medical SciencesGorganIran
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research CenterTabriz University of Medical SciencesTabrizIran
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27
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Benito-León M, Gil-Redondo JC, Perez-Sen R, Delicado EG, Ortega F, Gomez-Villafuertes R. BCI, an inhibitor of the DUSP1 and DUSP6 dual specificity phosphatases, enhances P2X7 receptor expression in neuroblastoma cells. Front Cell Dev Biol 2022; 10:1049566. [PMID: 36589747 PMCID: PMC9797830 DOI: 10.3389/fcell.2022.1049566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
P2X7 receptor (P2RX7) is expressed strongly by most human cancers, including neuroblastoma, where high levels of P2RX7 are correlated with a poor prognosis for patients. Tonic activation of P2X7 receptor favors cell metabolism and angiogenesis, thereby promoting cancer cell proliferation, immunosuppression, and metastasis. Although understanding the mechanisms that control P2X7 receptor levels in neuroblastoma cells could be biologically and clinically relevant, the intracellular signaling pathways involved in this regulation remain poorly understood. Here we show that (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), an allosteric inhibitor of dual specificity phosphatases (DUSP) 1 and 6, enhances the expression of P2X7 receptor in N2a neuroblastoma cells. We found that exposure to BCI induces the phosphorylation of mitogen-activated protein kinases p38 and JNK, while it prevents the phosphorylation of ERK1/2. BCI enhanced dual specificity phosphatase 1 expression, whereas it induced a decrease in the dual specificity phosphatase 6 transcripts, suggesting that BCI-dependent inhibition of dual specificity phosphatase 1 may be responsible for the increase in p38 and JNK phosphorylation. The weaker ERK phosphorylation induced by BCI was reversed by p38 inhibition, indicating that this MAPK is involved in the regulatory loop that dampens ERK activity. The PP2A phosphatase appears to be implicated in the p38-dependent dephosphorylation of ERK1/2. In addition, the PTEN phosphatase inhibition also prevented ERK1/2 dephosphorylation, probably through p38 downregulation. By contrast, inhibition of the p53 nuclear factor decreased ERK phosphorylation, probably enhancing the activity of p38. Finally, the inhibition of either p38 or Sp1-dependent transcription halved the increase in P2X7 receptor expression induced by BCI. Moreover, the combined inhibition of both p38 and Sp1 completely prevented the effect exerted by BCI. Together, our results indicate that dual specificity phosphatase 1 acts as a novel negative regulator of P2X7 receptor expression in neuroblastoma cells due to the downregulation of the p38 pathway.
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Affiliation(s)
- María Benito-León
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University Complutense of Madrid, Madrid, Spain,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain,Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Juan Carlos Gil-Redondo
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University Complutense of Madrid, Madrid, Spain,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain,Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain,Department of Nanobiotechnology, Institute for Biophysics, BOKU University for Natural Resources and Life Sciences, Vienna, Austria
| | - Raquel Perez-Sen
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University Complutense of Madrid, Madrid, Spain,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain,Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Esmerilda G. Delicado
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University Complutense of Madrid, Madrid, Spain,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain,Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Felipe Ortega
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University Complutense of Madrid, Madrid, Spain,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain,Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain,*Correspondence: Felipe Ortega, ; Rosa Gomez-Villafuertes,
| | - Rosa Gomez-Villafuertes
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University Complutense of Madrid, Madrid, Spain,Instituto Universitario de Investigación en Neuroquímica (IUIN), Madrid, Spain,Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain,*Correspondence: Felipe Ortega, ; Rosa Gomez-Villafuertes,
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28
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Alnafisah R, Lundh A, Asah SM, Hoeflinger J, Wolfinger A, Hamoud AR, McCullumsmith RE, O'Donovan SM. Altered purinergic receptor expression in the frontal cortex in schizophrenia. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2022; 8:96. [PMID: 36376358 PMCID: PMC9663420 DOI: 10.1038/s41537-022-00312-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 11/03/2022] [Indexed: 04/27/2023]
Abstract
ATP functions as a neurotransmitter, acting on the ubiquitously expressed family of purinergic P2 receptors. In schizophrenia (SCZ), the pathways that modulate extracellular ATP and its catabolism to adenosine are dysregulated. However, the effects of altered ATP availability on P2 receptor expression in the brain in SCZ have not been assessed. We assayed P2 receptor mRNA and protein expression in the DLPFC and ACC in subjects diagnosed with SCZ and matched, non-psychiatrically ill controls (n = 20-22/group). P2RX7, P2RX4 and male P2RX5 mRNA expression were significantly increased (p < 0.05) in the DLPFC in SCZ. Expression of P2RX7 protein isoform was also significantly increased (p < 0.05) in the DLPFC in SCZ. Significant increases in P2RX4 and male P2RX5 mRNA expression may be associated with antipsychotic medication effects. We found that P2RX4 and P2RX7 mRNA are significantly correlated with the inflammatory marker SERPINA3, and may suggest an association between upregulated P2XR and neuroinflammation in SCZ. These findings lend support for brain-region dependent dysregulation of the purinergic system in SCZ.
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Affiliation(s)
- Rawan Alnafisah
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
| | - Anna Lundh
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
| | - Sophie M Asah
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
| | - Julie Hoeflinger
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
| | - Alyssa Wolfinger
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
| | | | - Robert E McCullumsmith
- Department of Neurosciences, University of Toledo, Toledo, OH, USA
- Neurosciences Institute, Promedica, Toledo, OH, USA
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29
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Jackson T, Seifi M, Górecki DC, Swinny JD. Specific Dystrophins Selectively Associate with Inhibitory and Excitatory Synapses of the Mouse Cerebellum and their Loss Alters Expression of P2X7 Purinoceptors and Pro-Inflammatory Mediators. Cell Mol Neurobiol 2022; 42:2357-2377. [PMID: 34101068 PMCID: PMC9418305 DOI: 10.1007/s10571-021-01110-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 05/27/2021] [Indexed: 02/07/2023]
Abstract
Duchenne muscular dystrophy (DMD) patients, having mutations of the DMD gene, present with a range of neuropsychiatric disorders, in addition to the quintessential muscle pathology. The neurobiological basis remains poorly understood because the contributions of different DMD gene products (dystrophins) to the different neural networks underlying such symptoms are yet to be fully characterised. While full-length dystrophin clusters in inhibitory synapses, with inhibitory neurotransmitter receptors, the precise subcellular expression of truncated DMD gene products with excitatory synapses remains unresolved. Furthermore, inflammation, involving P2X purinoceptor 7 (P2RX7) accompanies DMD muscle pathology, yet any association with brain dystrophins is yet to be established. The aim of this study was to investigate the comparative expression of different dystrophins, alongside ionotropic glutamate receptors and P2RX7s, within the cerebellar circuitry known to express different dystrophin isoforms. Immunoreactivity for truncated DMD gene products was targeted to Purkinje cell (PC) distal dendrites adjacent to, or overlapping with, signal for GluA1, GluA4, GluN2A, and GluD2 receptor subunits. P2X7R immunoreactivity was located in Bergmann glia profiles adjacent to PC-dystrophin immunoreactivity. Ablation of all DMD gene products coincided with decreased mRNA expression for Gria2, Gria3, and Grin2a and increased GluD2 immunoreactivity. Finally, dystrophin-null mice showed decreased brain mRNA expression of P2rx7 and several inflammatory mediators. The data suggest that PCs target different dystrophin isoforms to molecularly and functionally distinct populations of synapses. In contrast to muscle, dystrophinopathy in brain leads to the dampening of the local immune system.
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Affiliation(s)
- Torquil Jackson
- School of Pharmacy & Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth, PO12DT, UK
| | - Mohsen Seifi
- Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK
| | - Dariusz C Górecki
- School of Pharmacy & Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth, PO12DT, UK
- Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-001, Warsaw, Poland
| | - Jerome D Swinny
- School of Pharmacy & Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth, PO12DT, UK.
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30
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Arnaud-Sampaio VF, Bento CA, Glaser T, Adinolfi E, Ulrich H, Lameu C. P2X7 receptor isoform B is a key drug resistance mediator for neuroblastoma. Front Oncol 2022; 12:966404. [PMID: 36091161 PMCID: PMC9458077 DOI: 10.3389/fonc.2022.966404] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Drug resistance is a major challenge for all oncological treatments that involve the use of cytotoxic agents. Recent therapeutic alternatives cannot circumvent the ability of cancer cells to adapt or alter the natural selection of resistant cells, so the problem persists. In neuroblastoma, recurrence can occur in up to 50% of high-risk patients. Therefore, the identification of novel therapeutic targets capable of modulating survival or death following classical antitumor interventions is crucial to address this problem. In this study, we investigated the role of the P2X7 receptor in chemoresistance. Here, we elucidated the contributions of P2X7 receptor A and B isoforms to neuroblastoma chemoresistance, demonstrating that the B isoform favors resistance through a combination of mechanisms involving drug efflux via MRP-type transporters, resistance to retinoids, retaining cells in a stem-like phenotype, suppression of autophagy, and EMT induction, while the A isoform has opposite and complementary roles.
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Affiliation(s)
| | - Carolina Adriane Bento
- Biochemistry Department, Institute of Chemistry, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Talita Glaser
- Biochemistry Department, Institute of Chemistry, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Elena Adinolfi
- Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Henning Ulrich
- Biochemistry Department, Institute of Chemistry, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Claudiana Lameu
- Biochemistry Department, Institute of Chemistry, University of Sao Paulo, Sao Paulo, SP, Brazil
- *Correspondence: Claudiana Lameu,
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31
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Aria H, Rezaei M, Nazem S, Daraei A, Nikfar G, Mansoori B, Bahmanyar M, Tavassoli A, Vakil MK, Mansoori Y. Purinergic receptors are a key bottleneck in tumor metabolic reprogramming: The prime suspect in cancer therapeutic resistance. Front Immunol 2022; 13:947885. [PMID: 36072596 PMCID: PMC9444135 DOI: 10.3389/fimmu.2022.947885] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
ATP and other nucleoside phosphates have specific receptors named purinergic receptors. Purinergic receptors and ectonucleotidases regulate various signaling pathways that play a role in physiological and pathological processes. Extracellular ATP in the tumor microenvironment (TME) has a higher level than in normal tissues and plays a role in cancer cell growth, survival, angiogenesis, metastasis, and drug resistance. In this review, we investigated the role of purinergic receptors in the development of resistance to therapy through changes in tumor cell metabolism. When a cell transforms to neoplasia, its metabolic processes change. The metabolic reprogramming modified metabolic feature of the TME, that can cause impeding immune surveillance and promote cancer growth. The purinergic receptors contribute to therapy resistance by modifying cancer cells' glucose, lipid, and amino acid metabolism. Limiting the energy supply of cancer cells is one approach to overcoming resistance. Glycolysis inhibitors which reduce intracellular ATP levels may make cancer cells more susceptible to anti-cancer therapies. The loss of the P2X7R through glucose intolerance and decreased fatty acid metabolism reduces therapeutic resistance. Potential metabolic blockers that can be employed in combination with other therapies will aid in the discovery of new anti-cancer immunotherapy to overcome therapy resistance. Therefore, therapeutic interventions that are considered to inhibit cancer cell metabolism and purinergic receptors simultaneously can potentially reduce resistance to treatment.
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Affiliation(s)
- Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Nazem
- Department of Laboratory Medicine, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolreza Daraei
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ghasem Nikfar
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Behnam Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Maryam Bahmanyar
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Alireza Tavassoli
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Mohammad Kazem Vakil
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran
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van Dijk A, Anten J, Bakker A, Evers N, Hoekstra AT, Chang JC, Scheenstra MR, Veldhuizen EJA, Netea MG, Berkers CR, Haagsman HP. Innate Immune Training of Human Macrophages by Cathelicidin Analogs. Front Immunol 2022; 13:777530. [PMID: 35958593 PMCID: PMC9360325 DOI: 10.3389/fimmu.2022.777530] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/15/2022] [Indexed: 11/21/2022] Open
Abstract
Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.
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Affiliation(s)
- Albert van Dijk
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
- *Correspondence: Albert van Dijk,
| | - Jennifer Anten
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Anne Bakker
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Noah Evers
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Anna T. Hoekstra
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
| | - Jung-Chin Chang
- Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Maaike R. Scheenstra
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Edwin J. A. Veldhuizen
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Mihai G. Netea
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
| | - Celia R. Berkers
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
- Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Henk P. Haagsman
- Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
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Zalpoor H, Akbari A, Nabi-Afjadi M, Forghaniesfidvajani R, Tavakol C, Barzegar Z, Iravanpour F, Hosseini M, Mousavi SR, Farrokhi MR. Hypoxia-inducible factor 1 alpha (HIF-1α) stimulated and P2X7 receptor activated by COVID-19, as a potential therapeutic target and risk factor for epilepsy. Hum Cell 2022; 35:1338-1345. [PMID: 35831562 PMCID: PMC9281298 DOI: 10.1007/s13577-022-00747-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/03/2022] [Indexed: 12/25/2022]
Abstract
Based on available evidence, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a neuroinvasive virus. According to the centers for disease control and prevention (CDC), coronavirus disease 2019 (COVID-19) may cause epilepsy. In this line, COVID-19 can stimulate hypoxia-inducible factor-1 alpha (HIF-1α) and activate P2X7 receptor. Both HIF-1α and P2X7 receptors are linked to epileptogenesis and seizures. Therefore, in the current study, we suggested that COVID-19 may have a role in epileptogenesis and seizure through HIF-1α stimulation and P2X7 receptor activation. Consequently, pharmacological targeting of these factors could be a promising therapeutic approach for such patients.
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Affiliation(s)
- Hamidreza Zalpoor
- Department of Neurosurgery, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. .,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
| | - Abdullatif Akbari
- Department of Neurosurgery, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Razieh Forghaniesfidvajani
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Chanour Tavakol
- Medical School, Tehran University of Medical Sciences, Tehran, Iran
| | - Zohreh Barzegar
- Department of Neurosurgery, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farideh Iravanpour
- Department of Neurosurgery, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahshid Hosseini
- Department of Neurosurgery, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Reza Mousavi
- Department of Neurosurgery, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Neurosurgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Majid Reza Farrokhi
- Department of Neurosurgery, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. .,Department of Neurosurgery, Shiraz University of Medical Sciences, Shiraz, Iran.
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P2X7 Receptors in Astrocytes: A Switch for Ischemic Tolerance. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123655. [PMID: 35744780 PMCID: PMC9228417 DOI: 10.3390/molecules27123655] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 11/17/2022]
Abstract
A sub-lethal ischemic episode (preconditioning [PC]) protects neurons against a subsequent lethal ischemic injury. This phenomenon is known as ischemic tolerance. PC itself does not cause brain damage, but affects glial responses, especially astrocytes, and transforms them into an ischemia-resistant phenotype. P2X7 receptors (P2X7Rs) in astrocytes play essential roles in PC. Although P2X7Rs trigger inflammatory and toxic responses, PC-induced P2X7Rs in astrocytes function as a switch to protect the brain against ischemia. In this review, we focus on P2X7Rs and summarize recent developments on how astrocytes control P2X7Rs and what molecular mechanisms they use to induce ischemic tolerance.
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Qiao C, Tang Y, Li Q, Zhu X, Peng X, Zhao R. ATP-gated P2X7 receptor as a potential target for prostate cancer. Hum Cell 2022; 35:1346-1354. [PMID: 35657562 DOI: 10.1007/s13577-022-00729-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/18/2022] [Indexed: 12/24/2022]
Abstract
Prostate cancer is the most common malignancy of the male genitourinary system and is one of the leading causes of male cancer death. The P2X7 receptor is an important member of purine receptor family. It is a gated ion channel with adenosine triphosphate (ATP) as the ligand, which exists in a variety of immune tissues and cells and can be involved in tumorigenesis and tumor progression. Studies have shown that the P2X7 receptor is abnormally expressed in prostate cancer, and is related to the level of prostate-specific antigen, P2X7 receptor may be an early biomarker of prostate cancer. The P2X7 receptor is essential in the occurrence and development of prostate cancer. The P2X7 receptor mainly affects the invasion and metastasis of prostate cancer cells through epithelial mesenchymal transition/invasion-related genes and the PI3K/AKT and ERK1/2 signaling pathways. The P2X7 receptor could be a promising therapeutic target for prostate cancer.
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Affiliation(s)
- Cuicui Qiao
- School of Laboratory Medicine, Weifang Medical University, Weifang, 261053, Shandong, China
| | - Yiqing Tang
- School of Laboratory Medicine, Weifang Medical University, Weifang, 261053, Shandong, China
| | - Qianqian Li
- School of Laboratory Medicine, Weifang Medical University, Weifang, 261053, Shandong, China
| | - Xiaodi Zhu
- School of Laboratory Medicine, Weifang Medical University, Weifang, 261053, Shandong, China
| | - Xiaoxiang Peng
- School of Laboratory Medicine, Weifang Medical University, Weifang, 261053, Shandong, China
| | - Ronglan Zhao
- School of Laboratory Medicine, Weifang Medical University, Weifang, 261053, Shandong, China.
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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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Vultaggio-Poma V, Falzoni S, Chiozzi P, Sarti AC, Adinolfi E, Giuliani AL, Sánchez-Melgar A, Boldrini P, Zanoni M, Tesei A, Pinton P, Di Virgilio F. Extracellular ATP is increased by release of ATP-loaded microparticles triggered by nutrient deprivation. Theranostics 2022; 12:859-874. [PMID: 34976217 PMCID: PMC8692914 DOI: 10.7150/thno.66274] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/16/2021] [Indexed: 02/06/2023] Open
Abstract
Rationale: Caloric restriction improves the efficacy of anti-cancer therapy. This effect is largely dependent on the increase of the extracellular ATP concentration in the tumor microenvironment (TME). Pathways for ATP release triggered by nutrient deprivation are largely unknown. Methods: The extracellular ATP (eATP) concentration was in vivo measured in the tumor microenvironment of B16F10-inoculated C57Bl/6 mice with the pmeLuc probe. Alternatively, the pmeLuc-TG-mouse was used. Caloric restriction was in vivo induced with hydroxycitrate (HC). B16F10 melanoma cells or CT26 colon carcinoma cells were in vitro exposed to serum starvation to mimic nutrient deprivation. Energy metabolism was monitored by Seahorse. Microparticle release was measured by ultracentrifugation and by Nanosight. Results: Nutrient deprivation increases eATP release despite the dramatic inhibition of intracellular energy synthesis. Under these conditions oxidative phosphorylation was dramatically impaired, mitochondria fragmented and glycolysis and lactic acid release were enhanced. Nutrient deprivation stimulated a P2X7-dependent release of ATP-loaded, mitochondria-containing, microparticles as well as of naked mitochondria. Conclusions: Nutrient deprivation promotes a striking accumulation of eATP paralleled by a large release of ATP-laden microparticles and of naked mitochondria. This is likely to be a main mechanism driving the accumulation of eATP into the TME.
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Di Virgilio F, Falzoni S, Sarti AC, Chiozzi P, Vultaggio-Poma V, Giuliani AL. Modulation of Cell Energy Metabolism by the P2X7 Receptor. Methods Mol Biol 2022; 2510:53-63. [PMID: 35776319 DOI: 10.1007/978-1-0716-2384-8_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
For many years the P2X7 receptor (P2X7R) was considered the prototypic cytolytic receptor due to its ability to cause dramatic changes in plasma membrane permeability, eventually leading to cell death. However, later studies revealed that controlled P2X7R activation has beneficial effects on cell metabolism and nowadays our perception of the physiological role of this receptor has radically changed. Some of the biochemical pathways underlying the trophic effect of the P2X7R are being unveiled, thus disclosing an unanticipated role of P2X7Rs in mitochondrial and glycolytic metabolism. We provide here an update of the effects of the P2X7R on cell energy metabolism.
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Affiliation(s)
| | - Simonetta Falzoni
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Alba Clara Sarti
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Paola Chiozzi
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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The Tyrosine Phosphatase hPTPRβ Controls the Early Signals and Dopaminergic Cells Viability via the P2X 7 Receptor. Int J Mol Sci 2021; 22:ijms222312936. [PMID: 34884741 PMCID: PMC8657974 DOI: 10.3390/ijms222312936] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/23/2021] [Accepted: 11/26/2021] [Indexed: 11/30/2022] Open
Abstract
ATP, one of the signaling molecules most commonly secreted in the nervous system and capable of stimulating multiple pathways, binds to the ionotropic purinergic receptors, in particular, the P2X7 receptor (P2X7R) and stimulates neuronal cell death. Given this effect of purinergic receptors on the viability of dopaminergic neurons model cells and that Ras GTPases control Erk1/2-regulated mitogen-activated cell proliferation and survival, we have investigated the role of the small GTPases of the Ras superfamily, together with their regulatory and effector molecules as the potential molecular intermediates in the P2X7R-regulated cell death of SN4741 dopaminergic neurons model cells. Here, we demonstrate that the neuronal response to purinergic stimulation involves the Calmodulin/RasGRF1 activation of the small GTPase Ras and Erk1/2. We also demonstrate that tyrosine phosphatase PTPRβ and other tyrosine phosphatases regulate the small GTPase activation pathway and neuronal viability. Our work expands the knowledge on the intracellular responses of dopaminergic cells by identifying new participating molecules and signaling pathways. In this sense, the study of the molecular circuitry of these neurons is key to understanding the functional effects of ATP, as well as considering the importance of these cells in Parkinson’s Disease.
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40
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P2X7 promotes metastatic spreading and triggers release of miRNA-containing exosomes and microvesicles from melanoma cells. Cell Death Dis 2021; 12:1088. [PMID: 34789738 PMCID: PMC8599616 DOI: 10.1038/s41419-021-04378-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/14/2021] [Accepted: 10/29/2021] [Indexed: 12/21/2022]
Abstract
Tumor growth and metastatic spreading are heavily affected by the P2X7 receptor as well as microvesicles and exosomes release into the tumor microenvironment. P2X7 receptor stimulation is known to trigger vesicular release from immune and central nervous system cells. However, P2X7 role in microvesicles and exosomes delivery from tumor cells was never analyzed in depth. Here we show that P2X7 is overexpressed in patients affected by metastatic malignant melanoma and that its expression closely correlates with reduced overall survival. Antagonism of melanoma cell-expressed P2X7 receptor inhibited in vitro anchorage-independent growth and migration and in vivo dissemination and lung metastasis formation. P2X7 stimulation triggered the release of miRNA-containing microvesicles and exosomes from melanoma cells, profoundly altering the nature of their miRNA content, as well as their dimensions and quantity. Among the more than 200 miRNAs that we found up-or-down-modulated for each vesicular fraction tested, we identified three miRNAs, miR-495-3p, miR-376c-3p, and miR-6730-3p, that were enriched in both the exosome and microvesicle fraction in a P2X7-dependent fashion. Interestingly, upon transfection, these miRNAs promoted melanoma cell growth or migration, and their vesicular release was minimized by P2X7 antagonism. Our data unveil an exosome/microvesicle and miRNA-dependent mechanism for the pro-metastatic activity of the P2X7 receptor and highlight this receptor as a suitable prognostic biomarker and therapeutic target in malignant melanoma.
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Hasan D, Shono A, van Kalken CK, van der Spek PJ, Krenning EP, Kotani T. A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling. Purinergic Signal 2021; 18:13-59. [PMID: 34757513 PMCID: PMC8578920 DOI: 10.1007/s11302-021-09814-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 07/18/2021] [Indexed: 12/15/2022] Open
Abstract
Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.
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Affiliation(s)
| | - Atsuko Shono
- Department of Anaesthesiology and Critical Care Medicine, School of Medicine, Showa University, Tokyo, 142-8666, Japan
| | | | - Peter J van der Spek
- Department of Pathology & Clinical Bioinformatics, Erasmus MC, Erasmus Universiteit Rotterdam, 3015 CE, Rotterdam, The Netherlands
| | | | - Toru Kotani
- Department of Anaesthesiology and Critical Care Medicine, School of Medicine, Showa University, Tokyo, 142-8666, Japan
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To inhibit or to boost the ATP/P2RX7 pathway to fight cancer-that is the question. Purinergic Signal 2021; 17:619-631. [PMID: 34347213 DOI: 10.1007/s11302-021-09811-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
Despite new biological insights and recent therapeutic advances, many tumors remain at baseline during treatments. Therefore, there is an urgent need to find new therapeutic strategies to improve the care of patients with solid tumors. P2RX7 receptor (P2XR7), an ATP-gated ion channel characterized by its ability to form large pore within the cell membrane, is described by most of the investigators as a "chef d'orchestre" of the antitumor immune response. The purpose of this review is to detail the recent information concerning different cellular mechanisms linking P2RX7 to hallmarks of cancer and to discuss different progresses in elucidating how activation of the ATP/P2RX7/NLRP3/IL-18 pathway is a very promising approach to fight cancer progression by increasing antitumor immune responses.
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Rabelo ILA, Arnaud-Sampaio VF, Adinolfi E, Ulrich H, Lameu C. Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor. Cells 2021; 10:1782. [PMID: 34359950 PMCID: PMC8305434 DOI: 10.3390/cells10071782] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/25/2021] [Accepted: 06/27/2021] [Indexed: 12/17/2022] Open
Abstract
The heterogeneity of tumor cell mass and the plasticity of cancer cell phenotypes in solid tumors allow for the insurgence of resistant and metastatic cells, responsible for cancer patients' clinical management's main challenges. Among several factors that are responsible for increased cancer aggression, metabolic reprogramming is recently emerging as an ultimate cancer hallmark, as it is central for cancer cell survival and self-renewal, metastasis and chemoresistance. The P2X7 receptor, whose expression is upregulated in many solid and hematological malignancies, is also emerging as a good candidate in cancer metabolic reprogramming and the regulation of stem cell proliferation and differentiation. Metabostemness refers to the metabolic reprogramming of cancer cells toward less differentiated (CSCs) cellular states, and we believe that there is a strong correlation between metabostemness and P2X7 receptor functions in oncogenic processes. Here, we summarize important aspects of P2X7 receptor functions in normal and tumor tissues as well as essential aspects of its structure, regulation, pharmacology and its clinical use. Finally, we review current knowledge implicating P2X7 receptor functions in cancer-related molecular pathways, in metabolic reprogramming and in metabostemness.
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Affiliation(s)
- Izadora Lorrany Alves Rabelo
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
| | - Vanessa Fernandes Arnaud-Sampaio
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
| | - Elena Adinolfi
- Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy;
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
| | - Claudiana Lameu
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
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The P2X7 Receptor: A Promising Pharmacological Target in Diabetic Retinopathy. Int J Mol Sci 2021; 22:ijms22137110. [PMID: 34281162 PMCID: PMC8268192 DOI: 10.3390/ijms22137110] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 12/29/2022] Open
Abstract
Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious complications of diabetes, and an established risk factor for blindness in adults. Over 15 years of investigation led to the identification of vascular endothelial growth factor (VEGF) as a main pathogenic factor in diabetic retinopathy and to the introduction of highly effective anti-VEGF-based therapies, such as the monoclonal antibody bevacizumab or its fragment ranibizumab, which helped to prevent diabetes-related blindness in millions of patients. Recently, a pathogenic role for uncontrolled increases in the extracellular ATP concentration (eATP) and for overactivation of the purinergic receptor P2X7 (P2X7R) has been suggested. The P2X7R is an eATP-gated plasma membrane channel expressed in multiple tissues and organs, with a pleiotropic function in inflammation, immunity, cancer, and hormone and growth factor release. P2X7R stimulation or overexpression positively regulate the secretion and buildup of VEGF, thus promoting neo-angiogenesis in a wide variety of disease processes. In this review, we explore current evidence that supports the role of P2X7R receptor signaling in the pathogenesis of diabetic retinopathy, as well as the most appealing current therapeutical options for P2X7R targeting.
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Grassi F, De Ponte Conti B. The P2X7 Receptor in Tumor Immunity. Front Cell Dev Biol 2021; 9:694831. [PMID: 34239877 PMCID: PMC8258391 DOI: 10.3389/fcell.2021.694831] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 05/25/2021] [Indexed: 01/01/2023] Open
Abstract
Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.
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Affiliation(s)
- Fabio Grassi
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland
| | - Benedetta De Ponte Conti
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
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P2X7 receptor in multifaceted cellular signalling and its relevance as a potential therapeutic target in different diseases. Eur J Pharmacol 2021; 906:174235. [PMID: 34097884 DOI: 10.1016/j.ejphar.2021.174235] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 05/28/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023]
Abstract
P2X7 receptor, a purinergic receptor family member, is abundantly expressed on many cells, including immune, muscle, bone, neuron, and glia. It acts as an ATP-activated cation channel that permits the influx of Ca2+, Na+ and efflux of K+ ions. The P2X7 receptor plays crucial roles in many physiological processes including cytokine and chemokine secretion, NLRP3 inflammasome activation, cellular growth and differentiation, locomotion, wound healing, transcription factors activation, cell death and T-lymphocyte survival. Past studies have demonstrated the up-regulation and direct association of this receptor in many pathophysiological conditions such as cancer, diabetics, arthritis, tuberculosis (TB) and inflammatory diseases. Hence, targeting this receptor is considered a worthwhile approach to lessen the afflictions associated with the disorders mentioned above by understanding the receptor architecture and downstream signalling processes. Here, in the present review, we have dissected the structural and functional aspects of the P2X7 receptor, emphasizing its role in various diseased conditions. This information will provide in-depth knowledge about the receptor and help to develop apt curative methodologies for the betterment of humanity in the coming years.
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Drill M, Jones NC, Hunn M, O'Brien TJ, Monif M. Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer. Purinergic Signal 2021; 17:215-227. [PMID: 33728582 PMCID: PMC8155177 DOI: 10.1007/s11302-021-09776-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on immune cells and is highly upregulated in a number of human cancers where it can play a trophic role in tumorigenesis. Activation of this receptor leads to the formation of a non-selective cation channel, which has been associated with several cellular functions mediated by the PI3K/Akt pathway and protein kinases. Due to its broad range of functions, the receptor represents a potential therapeutic target for a number of cancers. This review describes the range of mechanisms associated with P2X7R activation in cancer settings and highlights the potential of targeted inhibition of P2X7R as a therapy. It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts.
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Affiliation(s)
- Matthew Drill
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Physiology, Melbourne University, Parkville, VIC, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | - Nigel C Jones
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Martin Hunn
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Neurosurgery, Alfred Hospital, Melbourne, VIC, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | - Mastura Monif
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia.
- Department of Physiology, Melbourne University, Parkville, VIC, Australia.
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia.
- Department of Neurology, Melbourne Health, Parkville, VIC, Australia.
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Hasan F, Chiu Y, Shaw RM, Wang J, Yee C. Hypoxia acts as an environmental cue for the human tissue-resident memory T cell differentiation program. JCI Insight 2021; 6:138970. [PMID: 34027895 PMCID: PMC8262358 DOI: 10.1172/jci.insight.138970] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 04/07/2021] [Indexed: 12/31/2022] Open
Abstract
Tissue-resident memory T cells (TRM) provide frontline defense against infectious diseases and contribute to antitumor immunity; however, aside from the necessity of TGF-β, knowledge regarding TRM-inductive cues remains incomplete, particularly for human cells. Oxygen tension is an environmental cue that distinguishes peripheral tissues from the circulation, and here, we demonstrate that differentiation of human CD8+ T cells in the presence of hypoxia and TGF-β1 led to the development of a TRM phenotype, characterized by a greater than 5-fold increase in CD69+CD103+ cells expressing human TRM hallmarks and enrichment for endogenous human TRM gene signatures, including increased adhesion molecule expression and decreased expression of genes involved in recirculation. Hypoxia and TGF-β1 synergized to produce a significantly larger population of TRM phenotype cells than either condition alone, and comparison of these cells from the individual and combination conditions revealed distinct phenotypic and transcriptional profiles, indicating a programming response to milieu rather than a mere expansion. Our findings identify a likely previously unreported cue for the TRM differentiation program and can enable facile generation of human TRM phenotype cells in vitro for basic studies and translational applications such as adoptive cellular therapy.
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Affiliation(s)
- Farah Hasan
- Department of Melanoma Medical Oncology, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, USA.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Yulun Chiu
- Department of Melanoma Medical Oncology, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, USA
| | - Rebecca M Shaw
- Department of Melanoma Medical Oncology, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, USA
| | - Junmei Wang
- Department of Melanoma Medical Oncology, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, USA
| | - Cassian Yee
- Department of Melanoma Medical Oncology, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, USA.,Department of Immunology, UT MD Anderson Cancer Center, Houston, Texas, USA
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Elevated dimethylarginine, ATP, cytokines, metabolic remodeling involving tryptophan metabolism and potential microglial inflammation characterize primary open angle glaucoma. Sci Rep 2021; 11:9766. [PMID: 33963197 PMCID: PMC8105335 DOI: 10.1038/s41598-021-89137-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 04/20/2021] [Indexed: 02/03/2023] Open
Abstract
Glaucoma of which primary open angle glaucoma (POAG) constitutes 75%, is the second leading cause of blindness. Elevated intra ocular pressure and Nitric oxide synthase (NOS) dysfunction are hallmarks of POAG. We analyzed clinical data, cytokine profile, ATP level, metabolomics and GEO datasets to identify features unique to POAG. N9 microglial cells are used to gain mechanistic insights. Our POAG cohort showed elevated ATP in aqueous humor and cytokines in plasma. Metabolomic analysis showed changes in 21 metabolites including Dimethylarginine (DMAG) and activation of tryptophan metabolism in POAG. Analysis of GEO data sets and previously published proteomic data sets bins genes into signaling and metabolic pathways. Pathways from reanalyzed metabolomic data from literature significantly overlapped with those from our POAG data. DMAG modulated purinergic signaling, ATP secretion and cytokine expression were inhibited by N-Ethylmaleimide, NO donors, BAPTA and purinergic receptor inhibitors. ATP induced elevated intracellular calcium level and cytokines expression were inhibited by BAPTA. Metabolomics of cell culture supernatant from ATP treated sets showed metabolic deregulation and activation of tryptophan metabolism. DMAG and ATP induced IDO1/2 and TDO2 were inhibited by N-Ethylmaleimide, sodium nitroprusside and BAPTA. Our data obtained from clinical samples and cell culture studies reveal a strong association of elevated DMAG, ATP, cytokines and activation of tryptophan metabolism with POAG. DMAG mediated ATP signaling, inflammation and metabolic remodeling in microglia might have implications in management of POAG.
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Rivera AD, Chacon-De-La-Rocha I, Pieropan F, Papanikolau M, Azim K, Butt AM. Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors. Pflugers Arch 2021; 473:775-783. [PMID: 33712969 PMCID: PMC8076121 DOI: 10.1007/s00424-021-02544-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/04/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
White matter (WM) is a highly prominent feature in the human cerebrum and is comprised of bundles of myelinated axons that form the connectome of the brain. Myelin is formed by oligodendrocytes and is essential for rapid neuronal electrical communication that underlies the massive computing power of the human brain. Oligodendrocytes are generated throughout life by oligodendrocyte precursor cells (OPCs), which are identified by expression of the chondroitin sulphate proteoglycan NG2 (Cspg4), and are often termed NG2-glia. Adult NG2+ OPCs are slowly proliferating cells that have the stem cell-like property of self-renewal and differentiation into a pool of 'late OPCs' or 'differentiation committed' OPCs(COPs) identified by specific expression of the G-protein-coupled receptor GPR17, which are capable of differentiation into myelinating oligodendrocytes. In the adult brain, these reservoirs of OPCs and COPs ensure rapid myelination of new neuronal connections formed in response to neuronal signalling, which underpins learning and cognitive function. However, there is an age-related decline in myelination that is associated with a loss of neuronal function and cognitive decline. The underlying causes of myelin loss in ageing are manifold, but a key factor is the decay in OPC 'stemness' and a decline in their replenishment of COPs, which results in the ultimate failure of myelin regeneration. These changes in ageing OPCs are underpinned by dysregulation of neuronal signalling and OPC metabolic function. Here, we highlight the role of purine signalling in regulating OPC self-renewal and the potential importance of GPR17 and the P2X7 receptor subtype in age-related changes in OPC metabolism. Moreover, age is the main factor in the failure of myelination in chronic multiple sclerosis and myelin loss in Alzheimer's disease, hence understanding the importance of purine signalling in OPC regeneration and myelination is critical for developing new strategies for promoting repair in age-dependent neuropathology.
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Affiliation(s)
- Andrea D Rivera
- School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK
- Department of Neuroscience, Institute of Human Anatomy, University of Padua, Padua, Italy
| | | | - Francesca Pieropan
- School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK
| | - Maria Papanikolau
- School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK
| | - Kasum Azim
- Department of Neurology, Neuroregeneration, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Arthur M Butt
- School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK.
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