1
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Shukla S, Dalai P, Agrawal-Rajput R. Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy. Cell Signal 2024; 121:111281. [PMID: 38945420 DOI: 10.1016/j.cellsig.2024.111281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/02/2024]
Abstract
Adenosine 5'-triphosphate (ATP) is a vital element in energy information. It plays a critical role in transmitting signals inside the body, which is necessary for controlling the life activities of all cells, including tumor cells [1]. Its significance extends from intracellular signaling pathways to tumor regression. Purinergic signaling, a form of extracellular paracrine signaling, relies on purine nucleotides. Extracellular ectonucleotidases convert these purine nucleotides to their respective di and mono-phosphate nucleoside forms, contributing significantly to immune biology, cancer biology, and inflammation studies. ATP functions as a mighty damage-linked molecular pattern when released outside the cell, accumulating in inflammatory areas. In the tumor microenvironment (TME), purinergic receptors such as ATP-gated ion channels P2X1-5 and G protein-coupled receptors (GPCR) (P2Y) interact with ATP and other nucleotides, influencing diverse immune cell activities. CD39 and CD73-mediated extracellular ATP degradation contributes to immunosuppression by diminishing ATP-dependent activation and generating adenosine (ADO), potentially hindering antitumor immunity and promoting tumor development. Unraveling the complexities of extracellular ATP (e-ATP) and ADO effects on the TME poses challenges in identifying optimal treatment targets, yet ongoing investigations aim to devise strategies combating e-ATP/ADO-induced immunosuppression, ultimately enhancing anti-tumor immunity. This review explores e-ATP metabolism, its purinergic signaling, and therapeutic strategies targeting associated receptors and enzymes.
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Affiliation(s)
- Sourav Shukla
- Immunology Lab, Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar 382426, Gujarat, India
| | - Parameswar Dalai
- Immunology Lab, Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar 382426, Gujarat, India
| | - Reena Agrawal-Rajput
- Immunology Lab, Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar 382426, Gujarat, India.
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2
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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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3
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Zhang GP, Liao JX, Liu YY, Zhu FQ, Huang HJ, Zhang WJ. Ion channel P2X7 receptor in the progression of cancer. Front Oncol 2024; 13:1297775. [PMID: 38273855 PMCID: PMC10808724 DOI: 10.3389/fonc.2023.1297775] [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: 09/25/2023] [Accepted: 12/12/2023] [Indexed: 01/27/2024] Open
Abstract
P2X7 receptor (P2X7) is a non-selective and ATP-sensitive ligand-gated cation channel. Studies have confirmed that it is expressed in a variety of cells and correlates with their function, frequently in immune cells and tumor cells. We found increased expression of this receptor in many tumor cells, and it has a role in tumor survival and progression. In immune cells, upregulation of the receptor has a double effect on tumor suppression as well as tumor promotion. This review describes the structure of P2X7 and its role in the tumor microenvironment and presents possible mechanisms of P2X7 in tumor invasion and metastasis. Understanding the potential of P2X7 for tumor treatment, we also present several therapeutic agents targeting P2X7 and their mechanisms of action. In conclusion, the study of P2X7 is an important guideline for the use of clinical tumor therapy and may be able to provide a new idea for tumor treatment, but considering the complexity of the biological effects of P2X7, the drugs should be used with caution in clinical practice.
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Affiliation(s)
- Guang-ping Zhang
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
- Department of Critical Medicine, Ganzhou people’s Hospital, Ganzhou, Jiangxi, China
| | - Jun-xiang Liao
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yi-yi Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Fu-qi Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Hui-jin Huang
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-jun Zhang
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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4
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Zhang HL, Sandai D, Zhang ZW, Song ZJ, Babu D, Tabana Y, Dahham SS, Adam Ahmed Adam M, Wang Y, Wang W, Zhang HL, Zhao R, Barakat K, Harun MSR, Shapudin SNM, Lok B. Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy. World J Clin Oncol 2023; 14:549-569. [PMID: 38179405 PMCID: PMC10762532 DOI: 10.5306/wjco.v14.i12.549] [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: 09/06/2023] [Revised: 11/08/2023] [Accepted: 11/21/2023] [Indexed: 12/22/2023] Open
Abstract
Adenosine triphosphate (ATP) induced cell death (AICD) is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions. This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology. This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer. This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis, deciphering the intricate mechanisms governing AICD, elucidating its intricate involvement in cancer signaling pathways, and scrutinizing validated key genes. Moreover, the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Doblin Sandai
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Dinesh Babu
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Sabbar Saad Dahham
- Department of Science, University of Technology and Applied Sciences Rustaq, Rustaq 10 P.C. 329, Oman
| | - Mowaffaq Adam Ahmed Adam
- Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States
| | - Yong Wang
- Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Wei Wang
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Long Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Khaled Barakat
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Mohammad Syamsul Reza Harun
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Siti Nurfatimah Mohd Shapudin
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Bronwyn Lok
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
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5
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Shah Q, Hussain Z, Ahmad Khan B, Jacobson KA, Iqbal J. Synthesis and biological evaluation of carboxamide and quinoline derivatives as P2X7R antagonists. Bioorg Chem 2023; 140:106796. [PMID: 37683539 PMCID: PMC10544280 DOI: 10.1016/j.bioorg.2023.106796] [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: 05/18/2023] [Revised: 08/14/2023] [Accepted: 08/17/2023] [Indexed: 09/10/2023]
Abstract
P2X7 receptor (P2X7R) has a key role in different pathological conditions, importantly overexpressed and activated in cancers. We explored the structure activity relationship (SAR) of three novel pyrazines, quinoline-carboxamide and oxadiazole series. Their selective inhibitory potency in Ca2+ mobilization assay using h-P2X7R-MCF-7 cells improved with phenyl ring substitutions (-OCF3, -CF3, and -CH3) in carboxamide and oxadiazole derivatives, respectively. However, highly electronegative fluoro, chloro, and iodo substitutions enhanced affinity. 1e, 2f, 2e, 1d, 2 g and 3e were most potent and selective toward h-P2X7R (IC50 values 0.457, 0.566, 0.624, 0.682, 0.813 and 0.890 µM, respectively) and were inactive at h-P2X4R, h-P2X2R, r-P2Y6R, h-P2Y2R, t-P2Y1R expressed in MCF-7 and 1321N1 astrocytoma cells. Cell viability (MTT assay at 100 µM, cell line) for 3e was 62% (HEK-293T), 70% (1321N1 astrocytoma) and 85% (MCF-7). >75% cell viability was noted for 2 g and >80% for 2e and 1d in all non-transfected cell lines. Anti-proliferative effects, compared to control (Bz-ATP), of selective antagonists (10 µM) were 3e (11%) 1d, (19%) 1e, (70%, P = 0.005) and 2f, (24%), indicating involvement of P2X7R. Apoptotic cell death by flow cytometry showed 1e to be most promising, with 35% cell death (PI positive cells), followed by 2e (25%), 2f (20%), and 1d (19%), compared to control. Fluorescence microscopic analysis of apoptotic changes in P2X7R-transfected cell lines was established. 1e and 2f at 1X and 2X IC50 increased cellular shrinkage, nuclear condensation and PI/DAPI fluorescence. In-silico antagonist modeling predicted ligand receptor interactions, and all compounds obeyed Lipinski rules. These results suggest that pyrazine, quinoline-carboxamide and oxadiazole derivatives could be moderately potent P2X7R antagonists for in vivo studies and anti-cancer drug development.
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Affiliation(s)
- Qasim Shah
- Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan
| | - Zahid Hussain
- Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan
| | - Bilal Ahmad Khan
- Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad 13100, Pakistan
| | - Kenneth A Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD 20892, USA.
| | - Jamshed Iqbal
- Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan; Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
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6
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Mafra JCM, Boechat N, Teixeira GP, Faria RX. Synthetic molecules as P2X7 receptor antagonists: A medicinal chemistry update focusing the therapy of inflammatory diseases. Eur J Pharmacol 2023; 957:175999. [PMID: 37619787 DOI: 10.1016/j.ejphar.2023.175999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/12/2023] [Accepted: 08/17/2023] [Indexed: 08/26/2023]
Abstract
Stimulation of the P2X7 receptor by extracellular adenosine 5'-triphosphate induces a series of responses in the organism, exceptionally protein cascades related to the proinflammatory process. This has made P2X7 a target for research on inflammatory diseases such as rheumatoid arthritis. Thus, the incessant search for new prototypes that aim to antagonize the action of P2X7 has been remarkable in recent decades, a factor that has already led to numerous clinical studies in humans. In this review, we present the key molecules developed over the years with potential inhibition of P2X7 and inflammation. In addition, an update with newly developed chemical classes with promising activity and results in clinical studies for human pathologies focusing on P2X7 inhibition.
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Affiliation(s)
- João Carlos Martins Mafra
- Laboratório de Síntese de Fármacos (LASFAR) - Farmanguinhos - Fiocruz Brazil; Instituto Federal do Rio de Janeiro - IFRJ, Rio de Janeiro, Brazil.
| | - Nubia Boechat
- Laboratório de Síntese de Fármacos (LASFAR) - Farmanguinhos - Fiocruz Brazil.
| | - Guilherme Pegas Teixeira
- Laboratório de Avaliação e Promoção da Saúde Ambiental, Instituto Oswaldo Cruz (IOC), Rio de Janeiro Fiocruz Brazil.
| | - Robson Xavier Faria
- Laboratório de Avaliação e Promoção da Saúde Ambiental, Instituto Oswaldo Cruz (IOC), Rio de Janeiro Fiocruz Brazil.
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7
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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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8
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Bandara V, Foeng J, Gundsambuu B, Norton TS, Napoli S, McPeake DJ, Tyllis TS, Rohani-Rad E, Abbott C, Mills SJ, Tan LY, Thompson EJ, Willet VM, Nikitaras VJ, Zheng J, Comerford I, Johnson A, Coombs J, Oehler MK, Ricciardelli C, Cowin AJ, Bonder CS, Jensen M, Sadlon TJ, McColl SR, Barry SC. Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7. Nat Commun 2023; 14:5546. [PMID: 37684239 PMCID: PMC10491676 DOI: 10.1038/s41467-023-41338-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cell immunotherapy is a novel treatment that genetically modifies the patients' own T cells to target and kill malignant cells. However, identification of tumour-specific antigens expressed on multiple solid cancer types, remains a major challenge. P2X purinoceptor 7 (P2X7) is a cell surface expressed ATP gated cation channel, and a dysfunctional version of P2X7, named nfP2X7, has been identified on cancer cells from multiple tissues, while being undetectable on healthy cells. We present a prototype -human CAR-T construct targeting nfP2X7 showing potential antigen-specific cytotoxicity against twelve solid cancer types (breast, prostate, lung, colorectal, brain and skin). In xenograft mouse models of breast and prostate cancer, CAR-T cells targeting nfP2X7 exhibit robust anti-tumour efficacy. These data indicate that nfP2X7 is a suitable immunotherapy target because of its broad expression on human tumours. CAR-T cells targeting nfP2X7 have potential as a wide-spectrum cancer immunotherapy for solid tumours in humans.
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Affiliation(s)
- Veronika Bandara
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Jade Foeng
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Batjargal Gundsambuu
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Todd S Norton
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Silvana Napoli
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Dylan J McPeake
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Timona S Tyllis
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Elaheh Rohani-Rad
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Caitlin Abbott
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Stuart J Mills
- University of South Australia, STEM (Future Industries Institute) SA, Adelaide, 5095, Australia
| | - Lih Y Tan
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5001, Australia
| | - Emma J Thompson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5001, Australia
| | - Vasiliki M Willet
- Reproductive Cancer Research Group, Discipline Obstetrics and Gynaecology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Victoria J Nikitaras
- Reproductive Cancer Research Group, Discipline Obstetrics and Gynaecology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Jieren Zheng
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Iain Comerford
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Adam Johnson
- Seattle Children's Research Institute, Seattle, WA, 98101, USA
| | - Justin Coombs
- Carina Biotech, Level 2 Innovation & Collaboration Centre, UniSA Bradley Building, Adelaide, SA, 5001, Australia
| | - Martin K Oehler
- Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, SA, 5005, Australia
| | - Carmela Ricciardelli
- Reproductive Cancer Research Group, Discipline Obstetrics and Gynaecology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Allison J Cowin
- University of South Australia, STEM (Future Industries Institute) SA, Adelaide, 5095, Australia
| | - Claudine S Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5001, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Michael Jensen
- Seattle Children's Research Institute, Seattle, WA, 98101, USA
| | - Timothy J Sadlon
- Department of Gastroenterology, Women's and Children's Health Network, North Adelaide, SA, 5006, Australia
| | - Shaun R McColl
- Chemokine Biology Laboratory, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
- Carina Biotech, Level 2 Innovation & Collaboration Centre, UniSA Bradley Building, Adelaide, SA, 5001, Australia
| | - Simon C Barry
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5000, Australia.
- Carina Biotech, Level 2 Innovation & Collaboration Centre, UniSA Bradley Building, Adelaide, SA, 5001, Australia.
- Department of Gastroenterology, Women's and Children's Health Network, North Adelaide, SA, 5006, Australia.
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9
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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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10
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Purinergic P2X7R as a potential target for pancreatic cancer. Clin Transl Oncol 2023:10.1007/s12094-023-03123-7. [PMID: 36856920 DOI: 10.1007/s12094-023-03123-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/11/2023] [Indexed: 03/02/2023]
Abstract
Pancreatic cancer is one of the deadliest types of cancer, with a death rate nearly equal to the incidence. The P2X7 receptor (P2X7R) is a kind of extracellular adenosine triphosphate (ATP)-gated ion channel with special permeability, which exists in most tissues of human body and mediates inflammation-related signaling pathways and immune signal transduction after activation. P2X7R is also present on the surface of several tumor cells and is involved in tumor growth and progression. P2X7R expression in pancreatic cancer has also been identified in recent studies. Activation of P2X7R in pancreatic cancer can support the proliferation of pancreatic stellate cells, participate in protein interactions, and mediate ERK1/2, IL-6/STAT3, hCAP-18/LL-37, PI3K/AKT signaling pathways to promote pancreatic cancer progression. Inhibitors targeting P2X7R can inhibit the development of pancreatic cancer and are expected to be used in clinical therapy. Therefore, P2X7R is promising as a potential therapeutic target for pancreatic cancer. This article reviews the progress of research on P2X7R in pancreatic cancer.
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11
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Tang Y, Qiao C, Li Q, Zhu X, Zhao R, Peng X. Research Progress in the Relationship Between P2X7R and Cervical Cancer. Reprod Sci 2023; 30:823-834. [PMID: 35799022 DOI: 10.1007/s43032-022-01022-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 06/16/2022] [Indexed: 11/28/2022]
Abstract
Cervical cancer is one of the most common and serious tumors in women. Finding new biomarkers and therapeutic targets plays an important role in the diagnosis, prognosis, and treatment of cervical cancer. Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a purine ligand cation channel, activated by adenosine triphosphate (ATP). Studies have shown that P2X7R plays an important role in a variety of diseases and cancers. More and more studies have shown that P2X7R is also closely related to cervical cancer; therefore, the role of P2X7R in the development of cervical cancer deserves further discussion. The expression level of P2X7R in uterine epithelial cancer tissues was lower than that of the corresponding normal tissues. P2X7R plays an important role in the apoptotic process of cervical cancer through various mechanisms of action, and both antagonists and agonists of P2X7R can inhibit the proliferation of cervical cancer cells, while P2X7R is involved in the antitumor effect of Atr-I on cervical cancer cells. This review evaluates the current role of P2X7R in cervical cancer in order to develop more specific therapies for cervical cancer. In conclusion, P2X7R may become a biomarker for cervical cancer screening, and even a new target for clinical treatment of cervical cancer.
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Affiliation(s)
- Yiqing Tang
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Cuicui Qiao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Qianqian Li
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Xiaodi Zhu
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Ronglan Zhao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China.
| | - Xiaoxiang Peng
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China.
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12
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Kaur J, Dora S. Purinergic signaling: Diverse effects and therapeutic potential in cancer. Front Oncol 2023; 13:1058371. [PMID: 36741002 PMCID: PMC9889871 DOI: 10.3389/fonc.2023.1058371] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
Regardless of improved biological insights and therapeutic advances, cancer is consuming multiple lives worldwide. Cancer is a complex disease with diverse cellular, metabolic, and physiological parameters as its hallmarks. This instigates a need to uncover the latest therapeutic targets to advance the treatment of cancer patients. Purines are building blocks of nucleic acids but also function as metabolic intermediates and messengers, as part of a signaling pathway known as purinergic signaling. Purinergic signaling comprises primarily adenosine triphosphate (ATP) and adenosine (ADO), their analogous membrane receptors, and a set of ectonucleotidases, and has both short- and long-term (trophic) effects. Cells release ATP and ADO to modulate cellular function in an autocrine or paracrine manner by activating membrane-localized purinergic receptors (purinoceptors, P1 and P2). P1 receptors are selective for ADO and have four recognized subtypes-A1, A2A, A2B, and A3. Purines and pyrimidines activate P2 receptors, and the P2X subtype is ligand-gated ion channel receptors. P2X has seven subtypes (P2X1-7) and forms homo- and heterotrimers. The P2Y subtype is a G protein-coupled receptor with eight subtypes (P2Y1/2/4/6/11/12/13/14). ATP, its derivatives, and purinoceptors are widely distributed in all cell types for cellular communication, and any imbalance compromises the homeostasis of the cell. Neurotransmission, neuromodulation, and secretion employ fast purinergic signaling, while trophic purinergic signaling regulates cell metabolism, proliferation, differentiation, survival, migration, invasion, and immune response during tumor progression. Thus, purinergic signaling is a prospective therapeutic target in cancer and therapy resistance.
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Affiliation(s)
- Jasmeet Kaur
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Sanchit Dora
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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13
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Rossi C, Salvati A, Distaso M, Campani D, Raggi F, Biancalana E, Tricò D, Brunetto MR, Solini A. The P2X7R-NLRP3 and AIM2 Inflammasome Platforms Mark the Complexity/Severity of Viral or Metabolic Liver Damage. Int J Mol Sci 2022; 23:ijms23137447. [PMID: 35806450 PMCID: PMC9267345 DOI: 10.3390/ijms23137447] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 06/26/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD/NASH associated with chronic HCV infection than those with metabolic damage only (p ≤ 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.
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Affiliation(s)
- Chiara Rossi
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
| | - Antonio Salvati
- Azienda Ospedaliero-Universitaria Pisana, I-56126 Pisa, Italy;
| | - Mariarosaria Distaso
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
| | - Daniela Campani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, I-56126 Pisa, Italy;
| | - Francesco Raggi
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
| | - Edoardo Biancalana
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (E.B.); (D.T.)
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (E.B.); (D.T.)
| | - Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (E.B.); (D.T.)
- Correspondence: (M.R.B.); (A.S.); Tel.: +39-050-996857 (M.R.B.); +39-050-993482 (A.S.); Fax: +39-050-553235 (A.S.)
| | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy; (C.R.); (M.D.); (F.R.)
- Correspondence: (M.R.B.); (A.S.); Tel.: +39-050-996857 (M.R.B.); +39-050-993482 (A.S.); Fax: +39-050-553235 (A.S.)
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14
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Maynard JP, Sfanos KS. P2 purinergic receptor dysregulation in urologic disease. Purinergic Signal 2022; 18:267-287. [PMID: 35687210 PMCID: PMC9184359 DOI: 10.1007/s11302-022-09875-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/25/2022] [Indexed: 11/25/2022] Open
Abstract
P2 purinergic receptors are involved in the normal function of the kidney, bladder, and prostate via signaling that occurs in response to extracellular nucleotides. Dysregulation of these receptors is common in pathological states and often associated with disease initiation, progression, or aggressiveness. Indeed, P2 purinergic receptor expression is altered across multiple urologic disorders including chronic kidney disease, polycystic kidney disease, interstitial cystitis, urinary incontinence, overactive bladder syndrome, prostatitis, and benign prostatic hyperplasia. P2 purinergic receptors are likewise indirectly associated with these disorders via receptor-mediated inflammation and pain, a common characteristic across most urologic disorders. Furthermore, select P2 purinergic receptors are overexpressed in urologic cancer including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma, and pre-clinical studies depict P2 purinergic receptors as potential therapeutic targets. Herein, we highlight the compelling evidence for the exploration of P2 purinergic receptors as biomarkers and therapeutic targets in urologic cancers and other urologic disease. Likewise, there is currently optimism for P2 purinergic receptor-targeted therapeutics for the treatment of inflammation and pain associated with urologic diseases. Further exploration of the common pathways linking P2 purinergic receptor dysregulation to urologic disease might ultimately help in gaining new mechanistic insight into disease processes and therapeutic targeting.
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Affiliation(s)
- Janielle P Maynard
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.
| | - Karen S Sfanos
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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15
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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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16
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Zhao Y, Chen X, He C, Gao G, Chen Z, Du J. Discovery of bilirubin as novel P2X7R antagonist with anti-tumor activity. Bioorg Med Chem Lett 2021; 51:128361. [PMID: 34543755 DOI: 10.1016/j.bmcl.2021.128361] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/05/2021] [Accepted: 09/10/2021] [Indexed: 01/04/2023]
Abstract
As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphosphate (ATP) accumulated in the TME. High concentration of ATP can abnormally activate P2X7R, which induces pore formation and further facilitates the Ca2+ ion influx and non-specific substance intake. Therefore, inhibition of P2X7R activation can be applied as a potential anti-tumor therapy strategy. However, there is currently no FDA approved drugs for this target for anti-tumor treatment. In this study, we identified bilirubin as novel P2X7R antagonist by using structure based virtual screening combined with cell based assays. Molecular docking studies indicated that bilirubin probably interacted with P2X7R by forming hydrogen-π interactions with residues V173, E174 and K311. The compound bilirubin inhibited the P2X7R gated EB intake by cancer cells. Meanwhile, bilirubin was capable to inhibit the cell proliferation and migration of P2X7R expressed HT29 cells. The phosphorylation of mTOR, STAT3 and GSK3β were significantly decreased when bilirubin was present. Finally, in vivo experiment exhibited the anti-tumor effect of bilirubin in the MC38 bearing mice model, but did not show tissue damage in different organs. In conclusion, bilirubin was identified as a novel P2X7R antagonist and it may have potential for anti-cancer treatment, although various functions of the molecule should be considered.
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Affiliation(s)
- Yunshuo Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xiaotong Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Chuanjie He
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Guanfei Gao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jiangfeng Du
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
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17
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Dillard C, Borde C, Mohammad A, Puchois V, Jourdren L, Larsen AK, Sabbah M, Maréchal V, Escargueil AE, Pramil E. Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine. Int J Mol Sci 2021; 22:ijms222111472. [PMID: 34768902 PMCID: PMC8583864 DOI: 10.3390/ijms222111472] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/23/2022] Open
Abstract
The purine nucleotide adenosine triphosphate (ATP) is known for its fundamental role in cellular bioenergetics. However, in the last decades, different works have described emerging functions for ATP, such as that of a danger signaling molecule acting in the extracellular space on both tumor and stromal compartments. Beside its role in immune cell signaling, several studies have shown that high concentrations of extracellular ATP can directly or indirectly act on cancer cells. Accordingly, it has been reported that purinergic receptors are widely expressed in tumor cells. However, their expression pattern is often associated with contradictory cellular outcomes. In this work, we first investigated gene expression profiles through "RNA-Sequencing" (RNA Seq) technology in four colorectal cancer (CRC) cell lines (HT29, LS513, LS174T, HCT116). Our results demonstrate that CRC cells mostly express the A2B, P2X4, P2Y1, P2Y2 and P2Y11 purinergic receptors. Among these, the P2Y1 and P2Y2 coding genes are markedly overexpressed in all CRC cells compared to the HCEC-1CT normal-like colonic cells. We then explored the cellular outcomes induced by extracellular ATP and adenosine. Our results show that in terms of cell death induction extracellular ATP is consistently more active than adenosine against CRC, while neither compound affected normal-like colonic cell survival. Intriguingly, while for the P2Y2 receptor pharmacological inhibition completely abolished the rise in cytoplasmic Ca2+ observed after ATP exposure in all CRC cell lines, Ca2+ mobilization only impacted the cellular outcome for HT29. In contrast, non-selective phosphodiesterase inhibition completely abolished the effects of extracellular ATP on CRC cells, suggesting that cAMP and/or cGMP levels might determine cellular outcome. Altogether, our study provides novel insights into the characterization of purinergic signaling in CRC.
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Affiliation(s)
- Clémentine Dillard
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
| | - Chloé Borde
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
| | - Ammara Mohammad
- Genomics Core Facility, Institut de Biologie de l’ENS (IBENS), Département de Biologie, École Normale Supérieure, Université PSL, CNRS, INSERM, F-75005 Paris, France; (A.M.); (L.J.)
| | - Virginie Puchois
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
- Alliance for Research in Cancerology—APREC, Tenon Hospital, F-75020 Paris, France
| | - Laurent Jourdren
- Genomics Core Facility, Institut de Biologie de l’ENS (IBENS), Département de Biologie, École Normale Supérieure, Université PSL, CNRS, INSERM, F-75005 Paris, France; (A.M.); (L.J.)
| | - Annette K. Larsen
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
| | - Michèle Sabbah
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
| | - Vincent Maréchal
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
| | - Alexandre E. Escargueil
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
- Correspondence: ; Tel.: +33-1-49-28-46-44
| | - Elodie Pramil
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM U938, F-75012 Paris, France; (C.D.); (C.B.); (V.P.); (A.K.L.); (M.S.); (V.M.); (E.P.)
- Alliance for Research in Cancerology—APREC, Tenon Hospital, F-75020 Paris, France
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18
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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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19
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The P2X7 Receptor in the Maintenance of Cancer Stem Cells, Chemoresistance and Metastasis. Stem Cell Rev Rep 2021; 16:288-300. [PMID: 31813120 DOI: 10.1007/s12015-019-09936-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Metastasis is the worst prognosis predictor in the clinical course of cancer development. Features of metastatic cancer cells include migratory ability, low degree of differentiation, self-renewal and proliferation potentials, as well as resistance to therapies. Metastatic cells do not present all of the necessary characteristics at once. Indeed, they have a unique phenotypic plasticity, allowing the acquisition of features that make them successful in all steps of metastasis. Cancer stem cells (CSC), the most undifferentiated cells in the tumor mass, display highest metastatic potential and resistance to radio- and chemotherapy. Growing tumors exhibit marked upregulation of P2X7 receptor expression and secrete ATP. Since the P2X7 receptor plays an important role in the maintenance of undifferentiated state of pluripotent cells, its importance on cell fate regulation in the tumor mass is suggested. Considering the extensive crosstalk between CSCs, epithelial-mesenchymal transition, drug resistance and metastasis, current knowledge implicating P2X7 receptor function in these phenomena and new avenues for therapeutic strategies to control metastasis are reviewed.
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20
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Zhao Y, Chen X, Lyu S, Ding Z, Wu Y, Gao Y, Du J. Identification of novel P2X7R antagonists by using structure-based virtual screening and cell-based assays. Chem Biol Drug Des 2021; 98:192-205. [PMID: 33993620 DOI: 10.1111/cbdd.13867] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/30/2021] [Accepted: 05/08/2021] [Indexed: 12/13/2022]
Abstract
In the tumor microenvironment, inflammation and necrosis cause the accumulations of ATP extracellularly, and high concentrations of ATP can activate P2X7 receptors (P2X7R), which leads to the influx of Na+ , K+ , or Ca2+ into cells and trigger the downstream signaling pathways. P2X7R is a relatively unique ligand-gated ion channel, which is over-expressed in most tumor cells. The activated P2X7R facilitates the tumor growth, invasion, and metastasis. Inhibition of the P2X7R activation can be applied as a potential anti-tumor therapy strategy. There are currently no anti-tumor agents against P2X7R, though several P2X7R antagonists for indications such as anti-inflammatory and anti-depression were reported. In this study, we combined homology modeling (HM), virtual screening, and EB intake assay to characterize the structural features of P2X7R and identify several novel antagonists, which were chemically different from any other known P2X7R antagonists. The identified antagonists could effectively prevent the pore opening of P2X7R with IC50 values ranging from 29.14 to 35.34 μM. HM model showed the area between ATP-binding pocket, and allosteric sides were hydrophobic and suitable for small molecule interaction. Molecular docking indicated a universal binding mode, of which residues R294 and K311 were used as hydrogen bond donors to participate in antagonist interactions. The binding mode can potentially be utilized for inhibitor optimization for increased affinity, and the identified antagonists can be further tested for anti-cancer activity or may serve as chemical agents to study P2X7R related functions.
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Affiliation(s)
- Yunshuo Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiaotong Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Sifan Lyu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhe Ding
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yahong Wu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yanfeng Gao
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Jiangfeng Du
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
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21
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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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22
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Zhang WJ. Effect of P2X purinergic receptors in tumor progression and as a potential target for anti-tumor therapy. Purinergic Signal 2021; 17:151-162. [PMID: 33420658 PMCID: PMC7954979 DOI: 10.1007/s11302-020-09761-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
The development of tumors is a complex pathological process involving multiple factors, multiple steps, and multiple genes. Their prevention and treatment have always been a difficult problem at present. A large number of studies have proved that the tumor microenvironment plays an important role in the progression of tumors. The tumor microenvironment is the place where tumor cells depend for survival, and it plays an important role in regulating the growth, proliferation, apoptosis, migration, and invasion of tumor cells. P2X purinergic receptors, which depend on the ATP ion channel, can be activated by ATP in the tumor microenvironment, and by mediating tumor cells and related cells (such as immune cells) in the tumor microenvironment. They play an important regulatory role on the effects of the skeleton, membrane fluidity, and intracellular molecular metabolism of tumor cells. Therefore, here, we outlined the biological characteristics of P2X purinergic receptors, described the effect of tumor microenvironment on tumor progression, and discussed the effect of ATP on tumor. Moreover, we explored the role of P2X purinergic receptors in the development of tumors and anti-tumor therapy. These data indicate that P2X purinergic receptors may be used as another potential pharmacological target for tumor prevention and treatment.
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Affiliation(s)
- Wen-Jun Zhang
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang, 343000, Jiangxi, China.
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23
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Abstract
The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued.
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24
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Dutot M, Olivier E, Fouyet S, Magny R, Hammad K, Roulland E, Rat P, Fagon R. In Vitro Chemopreventive Potential of Phlorotannins-Rich Extract from Brown Algae by Inhibition of Benzo[a]pyrene-Induced P2X7 Activation and Toxic Effects. Mar Drugs 2021; 19:34. [PMID: 33466689 PMCID: PMC7828825 DOI: 10.3390/md19010034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 12/15/2022] Open
Abstract
Phlorotannins are polyphenols occurring exclusively in some species of brown algae, known for numerous biological activities, e.g., antioxidant, antiproliferative, antidiabetic, and antiallergic properties. Their effects on the response of human lung cells to benzo[a]pyrene (B[a]P) has not been characterized. Our objective was to in vitro evaluate the effects of a phlorotannin-rich extract obtained from the brown algae Ascophyllum nodosum and Fucus vesiculosus on B[a]P cytotoxic effects. The A549 cell line was incubated with B[a]P for 48 and 72 h in the presence or absence of the brown algae extract. Cytochrome P450 activity, activation of P2X7 receptor, F-actin disorganization, and loss of E-cadherin expression were assessed using microplate cytometry and fluorescence microscopy. Relative to control, incubation with the brown algae extract was associated with lower B[a]P-induced CYP1 activity, lower P2X7 receptor activation, and lower reactive oxygen species production. The brown algae extract inhibited the alterations of F-actin arrangement and the downregulation of E-cadherin expression. We identified a phlorotannins-rich extract that could be deeper investigated as a cancer chemopreventive agent to block B[a]P-mediated carcinogenesis.
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Affiliation(s)
- Mélody Dutot
- Recherche & Développement, Yslab, 29000 Quimper, France;
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Elodie Olivier
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Sophie Fouyet
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Romain Magny
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Karim Hammad
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Emmanuel Roulland
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Patrice Rat
- Faculté de Pharmacie de Paris, UMR CNRS 8038, Université de Paris, 75006 Paris, France; (E.O.); (S.F.); (R.M.); (K.H.); (E.R.); (P.R.)
| | - Roxane Fagon
- Recherche & Développement, Yslab, 29000 Quimper, France;
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25
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The P2X7 purinergic receptor: a potential therapeutic target for lung cancer. J Cancer Res Clin Oncol 2020; 146:2731-2741. [PMID: 32892231 DOI: 10.1007/s00432-020-03379-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 09/01/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Purinergic P2X7 receptor (P2X7R) is a gated ion channel for which adenosine triphosphate (ATP) is a ligand. Activated P2X7R is widely expressed in a variety of immune cells and tissues and is involved in a variety of physiological and pathological processes. Studies have confirmed that P2X7R is involved in the regulation of tumor cell growth, stimulating cell proliferation or inducing apoptosis. Recent studies have found that P2X7R is abnormally expressed in lung cancer and is closely related to the carcinogenesis and development of lung cancer. In this paper, we comprehensively describe the structure, function, and genetic polymorphisms of P2X7R. In particular, the role and therapeutic potential of P2X7R in lung cancer are discussed to provide new targets and new strategies for the treatment and prognosis of clinical lung cancer. METHODS The relevant literature on P2X7R and lung cancer from PubMed databases is reviewed in this article. RESULTS P2X7R regulates the function of lung cancer cells by activating multiple intracellular signaling pathways (such as the JNK, Rho, HMGB1 and EMT pathways), thereby affecting cell survival, growth, invasion, and metastasis and patient prognosis. Targeting P2X7R with inhibitors effectively suppresses the growth and metastasis of lung cancer cells. CONCLUSION In summary, P2X7R is expected to become a potential target for the treatment of lung cancer, and more clinical research is needed in the future to explore the effectiveness of P2X7R antagonists as treatments.
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Brisson L, Chadet S, Lopez-Charcas O, Jelassi B, Ternant D, Chamouton J, Lerondel S, Le Pape A, Couillin I, Gombault A, Trovero F, Chevalier S, Besson P, Jiang LH, Roger S. P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment. Cancers (Basel) 2020; 12:cancers12092342. [PMID: 32825056 PMCID: PMC7565976 DOI: 10.3390/cancers12092342] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/12/2020] [Accepted: 08/17/2020] [Indexed: 12/20/2022] Open
Abstract
The P2X7 receptor is an ATP-gated cation channel with a still ambiguous role in cancer progression, proposed to be either pro- or anti-cancerous, depending on the cancer or cell type in the tumour. Its role in mammary cancer progression is not yet defined. Here, we show that P2X7 receptor is functional in highly aggressive mammary cancer cells, and induces a change in cell morphology with fast F-actin reorganization and formation of filopodia, and promotes cancer cell invasiveness through both 2- and 3-dimensional extracellular matrices in vitro. Furthermore, P2X7 receptor sustains Cdc42 activity and the acquisition of a mesenchymal phenotype. In an immunocompetent mouse mammary cancer model, we reveal that the expression of P2X7 receptor in cancer cells, but not in the host mice, promotes tumour growth and metastasis development, which were reduced by treatment with specific P2X7 antagonists. Our results demonstrate that P2X7 receptor drives mammary tumour progression and represents a pertinent target for mammary cancer treatment.
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Affiliation(s)
- Lucie Brisson
- Inserm UMR1069-Nutrition, Growth and Cancer, University of Tours, 37032 Tours, France; (L.B.); (J.C.); (S.C.)
| | - Stéphanie Chadet
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Osbaldo Lopez-Charcas
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Bilel Jelassi
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - David Ternant
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Julie Chamouton
- Inserm UMR1069-Nutrition, Growth and Cancer, University of Tours, 37032 Tours, France; (L.B.); (J.C.); (S.C.)
| | - Stéphanie Lerondel
- CNRS UPS44 TAAM, PHENOMIN, Centre d’Imagerie du Petit Animal, 45071 Orléans, France; (S.L.); (A.L.P.)
| | - Alain Le Pape
- CNRS UPS44 TAAM, PHENOMIN, Centre d’Imagerie du Petit Animal, 45071 Orléans, France; (S.L.); (A.L.P.)
| | - Isabelle Couillin
- Laboratory of Molecular and Experimental Immunology and Neurogenetics, UMR 7355, CNRS, University of Orléans, 45071 Orléans, France; (I.C.); (A.G.)
| | - Aurélie Gombault
- Laboratory of Molecular and Experimental Immunology and Neurogenetics, UMR 7355, CNRS, University of Orléans, 45071 Orléans, France; (I.C.); (A.G.)
| | | | - Stéphan Chevalier
- Inserm UMR1069-Nutrition, Growth and Cancer, University of Tours, 37032 Tours, France; (L.B.); (J.C.); (S.C.)
| | - Pierre Besson
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
| | - Lin-Hua Jiang
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
- Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang 453003, China
| | - Sébastien Roger
- EA4245-Transplantation, Immunology and Inflammation, University of Tours, 37032 Tours, France; (S.C.); (O.L.-C.); (B.J.); (D.T.); (P.B.); (L.-H.J.)
- Institut Universitaire de France, 75005 Paris, France
- Correspondence: ; Tel.: +33-2-47-36-61-30
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27
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Andrejew R, Oliveira-Giacomelli Á, Ribeiro DE, Glaser T, Arnaud-Sampaio VF, Lameu C, Ulrich H. The P2X7 Receptor: Central Hub of Brain Diseases. Front Mol Neurosci 2020; 13:124. [PMID: 32848594 PMCID: PMC7413029 DOI: 10.3389/fnmol.2020.00124] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/17/2020] [Indexed: 12/27/2022] Open
Abstract
The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP). Upon long-term activation, it complexes with membrane proteins forming a wide pore that leads to cell death and increased release of ATP into the extracellular milieu. The P2X7 receptor is widely expressed in the CNS, such as frontal cortex, hippocampus, amygdala and striatum, regions involved in neurodegenerative diseases and psychiatric disorders. Despite P2X7 receptor functions in glial cells have been extensively studied, the existence and roles of this receptor in neurons are still controversially discussed. Regardless, P2X7 receptors mediate several processes observed in neuropsychiatric disorders and brain tumors, such as activation of neuroinflammatory response, stimulation of glutamate release and neuroplasticity impairment. Moreover, P2X7 receptor gene polymorphisms have been associated to depression, and isoforms of P2X7 receptors are implicated in neuropsychiatric diseases. In view of that, the P2X7 receptor has been proposed to be a potential target for therapeutic intervention in brain diseases. This review discusses the molecular mechanisms underlying P2X7 receptor-mediated signaling in neurodegenerative diseases, psychiatric disorders, and brain tumors. In addition, it highlights the recent advances in the development of P2X7 receptor antagonists that are able of penetrating the central nervous system.
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Affiliation(s)
- Roberta Andrejew
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | | | - Deidiane Elisa Ribeiro
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Talita Glaser
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | | | - Claudiana Lameu
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
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28
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Abstract
Ca2+ is a ubiquitous and dynamic second messenger molecule that is induced by many factors including receptor activation, environmental factors, and voltage, leading to pleiotropic effects on cell function including changes in migration, metabolism and transcription. As such, it is not surprising that aberrant regulation of Ca2+ signals can lead to pathological phenotypes, including cancer progression. However, given the highly context-specific nature of Ca2+-dependent changes in cell function, delineation of its role in cancer has been a challenge. Herein, we discuss the distinct roles of Ca2+ signaling within and between each type of cancer, including consideration of the potential of therapeutic strategies targeting these signaling pathways.
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Affiliation(s)
- Scott Gross
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Pranava Mallu
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Hinal Joshi
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Bryant Schultz
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Christina Go
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Jonathan Soboloff
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States; Department of Medical Genetics & Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.
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29
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Purinergic Signaling in the Hallmarks of Cancer. Cells 2020; 9:cells9071612. [PMID: 32635260 PMCID: PMC7407645 DOI: 10.3390/cells9071612] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/29/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.
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30
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Lara R, Adinolfi E, Harwood CA, Philpott M, Barden JA, Di Virgilio F, McNulty S. P2X7 in Cancer: From Molecular Mechanisms to Therapeutics. Front Pharmacol 2020; 11:793. [PMID: 32581786 PMCID: PMC7287489 DOI: 10.3389/fphar.2020.00793] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/13/2020] [Indexed: 12/18/2022] Open
Abstract
P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and post-translational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7.
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Affiliation(s)
- Romain Lara
- Biosceptre (UK) Limited, Cambridge, United Kingdom
| | - Elena Adinolfi
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Mike Philpott
- Centre for Cutaneous Research, Blizard Institute, Bart's & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | | | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
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31
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Stokes L, Bidula S, Bibič L, Allum E. To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors? Front Pharmacol 2020; 11:627. [PMID: 32477120 PMCID: PMC7235284 DOI: 10.3389/fphar.2020.00627] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/21/2020] [Indexed: 12/15/2022] Open
Abstract
The family of ligand-gated ion channels known as P2X receptors were discovered several decades ago. Since the cloning of the seven P2X receptors (P2X1-P2X7), a huge research effort has elucidated their roles in regulating a range of physiological and pathophysiological processes. Transgenic animals have been influential in understanding which P2X receptors could be new therapeutic targets for disease. Furthermore, understanding how inherited mutations can increase susceptibility to disorders and diseases has advanced this knowledge base. There has been an emphasis on the discovery and development of pharmacological tools to help dissect the individual roles of P2X receptors and the pharmaceutical industry has been involved in pushing forward clinical development of several lead compounds. During the discovery phase, a number of positive allosteric modulators have been described for P2X receptors and these have been useful in assigning physiological roles to receptors. This review will consider the major physiological roles of P2X1-P2X7 and discuss whether enhancement of P2X receptor activity would offer any therapeutic benefit. We will review what is known about identified compounds acting as positive allosteric modulators and the recent identification of drug binding pockets for such modulators.
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Affiliation(s)
- Leanne Stokes
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Stefan Bidula
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Lučka Bibič
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Elizabeth Allum
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
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32
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Ardura JA, Álvarez-Carrión L, Gutiérrez-Rojas I, Alonso V. Role of Calcium Signaling in Prostate Cancer Progression: Effects on Cancer Hallmarks and Bone Metastatic Mechanisms. Cancers (Basel) 2020; 12:E1071. [PMID: 32344908 PMCID: PMC7281772 DOI: 10.3390/cancers12051071] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/19/2020] [Accepted: 04/23/2020] [Indexed: 12/24/2022] Open
Abstract
Advanced prostate cancers that progress to tumor metastases are often considered incurable or difficult to treat. The etiology of prostate cancers is multi-factorial. Among other factors, de-regulation of calcium signals in prostate tumor cells mediates several pathological dysfunctions associated with tumor progression. Calcium plays a relevant role on tumor cell death, proliferation, motility-invasion and tumor metastasis. Calcium controls molecular factors and signaling pathways involved in the development of prostate cancer and its progression. Such factors and pathways include calcium channels and calcium-binding proteins. Nevertheless, the involvement of calcium signaling on prostate cancer predisposition for bone tropism has been relatively unexplored. In this regard, a diversity of mechanisms triggers transient accumulation of intracellular calcium in prostate cancer cells, potentially favoring bone metastases development. New therapies for the treatment of prostate cancer include compounds characterized by potent and specific actions that target calcium channels/transporters or pumps. These novel drugs for prostate cancer treatment encompass calcium-ATPase inhibitors, voltage-gated calcium channel inhibitors, transient receptor potential (TRP) channel regulators or Orai inhibitors. This review details the latest results that have evaluated the relationship between calcium signaling and progression of prostate cancer, as well as potential therapies aiming to modulate calcium signaling in prostate tumor progression.
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Affiliation(s)
- Juan A. Ardura
- Bone Physiopathology laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain; (J.A.A.); (L.Á.-C.); (I.G.-R.)
- Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain
| | - Luis Álvarez-Carrión
- Bone Physiopathology laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain; (J.A.A.); (L.Á.-C.); (I.G.-R.)
| | - Irene Gutiérrez-Rojas
- Bone Physiopathology laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain; (J.A.A.); (L.Á.-C.); (I.G.-R.)
| | - Verónica Alonso
- Bone Physiopathology laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain; (J.A.A.); (L.Á.-C.); (I.G.-R.)
- Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Madrid, Spain
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Feng LL, Cai YQ, Zhu MC, Xing LJ, Wang X. The yin and yang functions of extracellular ATP and adenosine in tumor immunity. Cancer Cell Int 2020; 20:110. [PMID: 32280302 PMCID: PMC7137337 DOI: 10.1186/s12935-020-01195-x] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 03/27/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular adenosine triphosphate (eATP) and its main metabolite adenosine (ADO) constitute an intrinsic part of immunological network in tumor immunity. The concentrations of eATP and ADO in tumor microenvironment (TME) are controlled by ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed on immune cells, endothelial cells and cancer cells. Once accumulated in TME, eATP boosts antitumor immune responses, while ADO attenuates immunity against tumors. eATP and ADO, like yin and yang, represent two opposite aspects from immune-activating to immune-suppressive signals. Here we reviewed the functions of eATP and ADO in tumor immunity and attempt to block eATP hydrolysis, ADO formation and their contradictory effects in tumor models, allowing the induction of effective anti-tumor immune responses in TME. These attempts documented that therapeutic approaches targeting eATP/ADO metabolism and function may be effective methods in cancer therapy.
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Affiliation(s)
- Li-Li Feng
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China
| | - Yi-Qing Cai
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China
| | - Ming-Chen Zhu
- 5Department of Clinical Laboratory, Nanjing Medical University Cancer Hospital & Jiangsu Cancer Hospital, Nanjing, 210009 Jiangsu China
| | - Li-Jie Xing
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China
| | - Xin Wang
- 1Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, Jinan, 250021 Shandong China.,2School of Medicine, Shandong University, Jinan, 250012 Shandong China.,Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021 Shandong China.,National clinical research center for hematologic diseases, Jinan, 250021 Shandong China
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Zyma M, Pawliczak R. Characteristics and the role of purinergic receptors in pathophysiology with focus on immune response. Int Rev Immunol 2020; 39:97-117. [PMID: 32037918 DOI: 10.1080/08830185.2020.1723582] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The nucleotide adenosine-5'-triphosphate (ATP) is mostly thought to be energy carrier, but evidence presented in multiple studies proves ATP involvement into variety of processes, due to its neuromodulatory capabilities. ATP and its metabolite-adenosine, bind to the purinergic receptors, which are divided into two types: adenosine binding P1 receptor and ADP/ATP binding P2 receptor. These receptors are expressed in different tissues and organs. Recent studies report their immunomodulatory characteristics, connected with varying immunological processes, such as immunological response or antigen presentation. Besides, they seem to play an important role in medical conditions such as bronchial asthma or variety of cancers. In this article, we would like to review recent discoveries on the field of purinergic receptors research focusing on their role in immunological system, and shed a new light upon the importance of these receptors in modern medicine development.
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Affiliation(s)
- Marharyta Zyma
- Department of Immunopathology, Division of Biomedical Science, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Rafał Pawliczak
- Department of Immunopathology, Division of Biomedical Science, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Goel P, Alam O, Naim MJ, Nawaz F, Iqbal M, Alam MI. Recent advancement of piperidine moiety in treatment of cancer- A review. Eur J Med Chem 2018; 157:480-502. [DOI: 10.1016/j.ejmech.2018.08.017] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 03/26/2018] [Accepted: 08/04/2018] [Indexed: 12/23/2022]
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ATP in the tumour microenvironment drives expression of nfP2X 7, a key mediator of cancer cell survival. Oncogene 2018; 38:194-208. [PMID: 30087439 PMCID: PMC6328436 DOI: 10.1038/s41388-018-0426-6] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 07/13/2018] [Accepted: 07/14/2018] [Indexed: 12/29/2022]
Abstract
The ATP-gated receptor P2X7 is expressed in multiple malignant tumours including neuroblastoma, melanoma, prostate, lung and breast. P2X7 has a significant role in mediating diverse cell responses, which upon dysregulation are associated with tumour initiation and development. The rapid, ATP-mediated activation of P2X7 induces a fast-inward cation current in cells. However, prolonged ATP-mediated activation of P2X7 leads to formation of a pore that increases membrane permeability and eventually causes cell death. This presents a potential paradox, as the tumour microenvironment contains extracellular ATP at levels sufficient to activate the P2X7 pore and trigger cell death. However, P2X7 expression is associated with enhanced cancer cell survival, proliferation and metastatic potential. At least one distinct conformational form of P2X7, termed non-pore functional P2X7 (nfP2X7), has been described, which is not able to form a functional pore. We demonstrate for the first time in this study that exposure to a high ATP concentration, equivalent to those measured in the tumour microenvironment, drives nfP2X7 expression and also that nfP2X7 is essential for tumour cell survival. We show that monoclonal antibodies raised against a P2X7 amino acid sequence (200–216), whose conformation is distinct from that of wild-type (WT) P2X7, bind specifically to nfP2X7 expressed on the surface of tumour cells. We also show that nfP2X7 is broadly expressed in patient-derived tumour sections from a wide range of cancers. Therefore, antibodies raised against E200 provide tools that can differentiate between forms of the P2X7 receptor that have a key role in cancer.
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Young CNJ, Górecki DC. P2RX7 Purinoceptor as a Therapeutic Target-The Second Coming? Front Chem 2018; 6:248. [PMID: 30003075 PMCID: PMC6032550 DOI: 10.3389/fchem.2018.00248] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 06/08/2018] [Indexed: 12/22/2022] Open
Abstract
The P2RX7 receptor is a unique member of a family of extracellular ATP (eATP)-gated ion channels expressed in immune cells, where its activation triggers the inflammatory cascade. Therefore, P2RX7 has been long investigated as a target in the treatment of infectious and inflammatory diseases. Subsequently, P2RX7 signaling has been documented in other physiological and pathological processes including pain, CNS and psychiatric disorders and cancer. As a result, a range of P2RX7 antagonists have been developed and trialed. Interestingly, the recent crystallization of mammalian and chicken receptors revealed that most widely-used antagonists may bind a unique allosteric site. The availability of crystal structures allows rational design of improved antagonists and modeling of binding sites of the known or presumed inhibitors. However, several unanswered questions limit the cogent development of P2RX7 therapies. Firstly, this receptor functions as an ion channel, but its chronic stimulation by high eATP causes opening of the non-selective large pore (LP), which can trigger cell death. Not only the molecular mechanism of LP opening is still not fully understood but its function(s) are also unclear. Furthermore, how can tumor cells take advantage of P2RX7 for growth and spread and yet survive overexpression of potentially cytotoxic LP in the eATP-rich environment? The recent discovery of the feedback loop, wherein the LP-evoked release of active MMP-2 triggers the receptor cleavage, provided one explanation. Another mechanism might be that of cancer cells expressing a structurally altered P2RX7 receptor, devoid of the LP function. Exploiting such mechanisms should lead to the development of new, less toxic anticancer treatments. Notably, targeted inhibition of P2RX7 is crucial as its global blockade reduces the immune and inflammatory responses, which have important anti-tumor effects in some types of malignancies. Therefore, another novel approach is the synthesis of tissue/cell specific P2RX7 antagonists. Progress has been aided by the development of p2rx7 knockout mice and new conditional knock-in and knock-out models are being created. In this review, we seek to summarize the recent advances in our understanding of molecular mechanisms of receptor activation and inhibition, which cause its re-emergence as an important therapeutic target. We also highlight the key difficulties affecting this development.
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Affiliation(s)
- Chris N. J. Young
- Molecular Medicine Laboratory, Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom
- Faculty of Health and Life Sciences, The School of Allied Health Sciences, De Montfort University, Leicester, United Kingdom
| | - Dariusz C. Górecki
- Molecular Medicine Laboratory, Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom
- The General Karol Kaczkowski Military Institute of Hygiene and Epidemiology, Warsaw, Poland
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Alves LA, Ferreira LB, Pacheco PF, Mendivelso EAC, Teixeira PCN, Faria RX. Pore forming channels as a drug delivery system for photodynamic therapy in cancer associated with nanoscintillators. Oncotarget 2018; 9:25342-25354. [PMID: 29861876 PMCID: PMC5982756 DOI: 10.18632/oncotarget.25150] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 03/27/2018] [Indexed: 01/05/2023] Open
Abstract
According to the World Health Organization (WHO), cancer is one of main causes of death worldwide, with 8.2 million people dying from this disease in 2012. Because of this, new forms of treatments or improvement of current treatments are crucial. In this regard, Photodynamic therapy (PDT) has been used to successfully treat cancers that can be easily accessed externally or by fibre-optic endoscopes, such as skin, bladder and esophagus cancers. In addition, this therapy can used alongside radiotherapy and chemotherapy in order to kill cancer cells. The main problem in implementing PDT is penetration of visible light deeper than 10 mm in tissues, due to scattering and absorption by tissue chromophores. Unfortunately, this excludes several internal organs affected by cancer. Another issue in this regard is the use of a selective cancer cell-photosensitizing compound. Nevertheless, several groups have recently developed scintillation nanoparticles, which can be stimulated by X-rays, thereby making this a possible solution for light production in deeper tissues. Alternative approaches have also been developed, such as photosensitizer structure modifications and cell membrane permeabilizing agents. In this context, certain channels lead to transitory plasma membrane permeability changes, such as pannexin, connexin hemmichannels, TRPV1-4 and P2×7, which allow for the non-selective passage of molecules up to 1,000 Da. Herein, we discuss the particular case of the P2×7 receptor-associated pore as a drug delivery system for hydrophilic substances to be applied in PDT, which could also be carried out with other channels. Methylene blue (MB) is a low cost dye used as a prototype photosensitizer, approved for clinical use in several other clinical conditions, as well as photodynamic therapy for fungi infections.
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Affiliation(s)
- Luiz Anastacio Alves
- Laboratório de Comunicação Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz-FIOCRUZ, 21045-900, Rio de Janeiro, RJ, Brasil
| | - Leonardo Braga Ferreira
- Laboratório de Inflamação e Instituto Oswaldo Cruz, Fundação Oswaldo Cruz-FIOCRUZ, 21045-900, Rio de Janeiro, RJ, Brasil
| | - Paulo Furtado Pacheco
- Laboratório de Toxoplasmose Instituto Oswaldo Cruz, Fundação Oswaldo Cruz-FIOCRUZ, 21045-900, Rio de Janeiro, RJ, Brasil
| | | | - Pedro Celso Nogueira Teixeira
- Laboratório de Comunicação Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz-FIOCRUZ, 21045-900, Rio de Janeiro, RJ, Brasil
| | - Robson Xavier Faria
- Laboratório de Toxoplasmose Instituto Oswaldo Cruz, Fundação Oswaldo Cruz-FIOCRUZ, 21045-900, Rio de Janeiro, RJ, Brasil
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Kwak SH, Shin S, Lee JH, Shim JK, Kim M, Lee SD, Lee A, Bae J, Park JH, Abdelrahman A, Müller CE, Cho SK, Kang SG, Bae MA, Yang JY, Ko H, Goddard WA, Kim YC. Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells. Eur J Med Chem 2018; 151:462-481. [PMID: 29649742 DOI: 10.1016/j.ejmech.2018.03.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 02/28/2018] [Accepted: 03/08/2018] [Indexed: 02/04/2023]
Abstract
Screening a compound library of quinolinone derivatives identified compound 11a as a new P2X7 receptor antagonist. To optimize its activity, we assessed structure-activity relationships (SAR) at three different positions, R1, R2 and R3, of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R1 position, an adamantyl carboxamide group at R2 and a 4-methoxy substitution at the R3 position are the best substituents for the antagonism of P2X7R activity. However, because most of the quinolinone derivatives showed low inhibitory effects in an IL-1β ELISA assay, the core structure was further modified to a quinoline skeleton with chloride or substituted phenyl groups. The optimized antagonists with the quinoline scaffold included 2-chloro-5-adamantyl-quinoline derivative (16c) and 2-(4-hydroxymethylphenyl)-5-adamantyl-quinoline derivative (17k), with IC50 values of 4 and 3 nM, respectively. In contrast to the quinolinone derivatives, the antagonistic effects of the quinoline compounds (16c and 17k) were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1β, from LPS/IFN-γ/BzATP-stimulated THP-1 cells (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.
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Affiliation(s)
- Seung-Hwa Kwak
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Seungheon Shin
- Department of BioMedical Science and Engineering (BMSE), Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
| | - Ji-Hyun Lee
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Jin-Kyoung Shim
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Minjeong Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - So-Deok Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Aram Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Jinsu Bae
- Department of BioMedical Science and Engineering (BMSE), Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
| | - Jin-Hee Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Aliaa Abdelrahman
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany
| | - Christa E Müller
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany
| | - Steve K Cho
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea; Department of BioMedical Science and Engineering (BMSE), Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
| | - Seok-Gu Kang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Myung Ae Bae
- Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea
| | - Jung Yoon Yang
- Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea
| | - Hyojin Ko
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea.
| | - William A Goddard
- Materials and Process Simulation Center (MC-139- 74), California Institute of Technology, Pasadena, California 91125, United States
| | - Yong-Chul Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea; Department of BioMedical Science and Engineering (BMSE), Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
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Burnstock G, Knight GE. The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. Purinergic Signal 2018; 14:1-18. [PMID: 29164451 PMCID: PMC5842154 DOI: 10.1007/s11302-017-9593-0] [Citation(s) in RCA: 185] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/01/2017] [Indexed: 12/22/2022] Open
Abstract
Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK.
- Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Australia.
- Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia.
| | - Gillian E Knight
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK
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Salvestrini V, Orecchioni S, Talarico G, Reggiani F, Mazzetti C, Bertolini F, Orioli E, Adinolfi E, Di Virgilio F, Pezzi A, Cavo M, Lemoli RM, Curti A. Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells. Oncotarget 2018; 8:5895-5908. [PMID: 27980223 PMCID: PMC5351599 DOI: 10.18632/oncotarget.13927] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 09/25/2016] [Indexed: 11/25/2022] Open
Abstract
Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2X7R is the most consistently expressed by tumors. P2X7R is an ATP-gated ion channel that could drive the opening of a non-selective pore, triggering cell-death signal. We previously demonstrated that acute myeloid leukemia (AML) cells express high level of P2X7R. Here, we show that P2X7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2X7R is also expressed on leukemic stem/progenitor cells (LSCs) which are sensitive to ATP-mediated cytotoxicity. Conversely, this cytotoxic effect was not observed on normal hematopoietic stem/progenitor cells (HSCs). Notably, the antileukemic activity of ATP was also observed in presence of bone marrow stromal cells and its addition to the culture medium enhanced cytosine arabinoside cytotoxicity despite stroma-induced chemoresistance. Xenotransplant experiments confirmed ATP antineoplastic activity in vivo.Overall, our results demonstrate that P2X7R stimulation by ATP induced a therapeutic response in AML at the LSC level while the normal stem cell compartment was not affected. These results provide evidence that ATP would be promising for developing innovative therapy for AML.
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Affiliation(s)
- Valentina Salvestrini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | | | | | | | - Cristina Mazzetti
- Department Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | | | - Elisa Orioli
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Elena Adinolfi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Annalisa Pezzi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Michele Cavo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Roberto M Lemoli
- Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
| | - Antonio Curti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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42
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Burnstock G. Purinergic Signalling: Therapeutic Developments. Front Pharmacol 2017; 8:661. [PMID: 28993732 PMCID: PMC5622197 DOI: 10.3389/fphar.2017.00661] [Citation(s) in RCA: 287] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 09/05/2017] [Indexed: 12/15/2022] Open
Abstract
Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990's when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson's disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical SchoolLondon, United Kingdom
- Department of Pharmacology and Therapeutics, The University of Melbourne, MelbourneVIC, Australia
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Gilbert SM, Gidley Baird A, Glazer S, Barden JA, Glazer A, Teh LC, King J. A phase I clinical trial demonstrates that nfP2X 7 -targeted antibodies provide a novel, safe and tolerable topical therapy for basal cell carcinoma. Br J Dermatol 2017; 177:117-124. [PMID: 28150889 DOI: 10.1111/bjd.15364] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND Expression of P2X7 , an ATP-gated calcium channel, increases cancer cell proliferation and invasiveness. A variant of P2X7 (termed nfP2X7 ), in which a normally hidden epitope (E200) is exposed for antibody binding, is observed in a variety of different cancers. OBJECTIVES To investigate the safety, tolerability and pharmacokinetics and assess indicative efficacy of a novel antibody ointment as a therapeutic for basal cell carcinoma (BCC). METHODS An open-label, phase I clinical trial was undertaken at three dermatology clinics to evaluate the safety and tolerability of topical administration of an ointment containing 10% sheep polyclonal anti-nfP2X7 antibodies (BIL010t) to primary BCC lesions twice daily for 28 days. Twenty-one patients with primary BCC lesions at least 0·5 cm2 in area and less than 2·0 cm in diameter were enrolled. The primary end points were safety, tolerability and pharmacokinetics. Change in lesion size after treatment was determined and histology was performed on pretreatment and end-of-treatment (EOT) biopsies. RESULTS Compliance was very high, with treatment being well tolerated. The most common adverse events were treatment site erythema, pruritus, dryness and pain. There was no evidence of systemic penetration of the sheep antibody. Lesions were measured prior to and after 28 days of treatment, with 65% of patients showing a reduction in lesion area, 20% showing no change and 15% showing an increase. Histopathology of post-treatment excision of lesion sites showed eight patients with stable disease, nine with partial response and three with complete response. CONCLUSIONS Antibodies against nfP2X7 (BIL010t) provide a novel, safe and well-tolerated treatment for BCC.
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Affiliation(s)
- S M Gilbert
- Babraham Research Campus, Biosceptre (U.K.) Limited, Cambridge, U.K
| | - A Gidley Baird
- Biosceptre (Australia) Pty Ltd., 11 Julius Avenue, North Ryde, NSW, 2113, Australia
| | - S Glazer
- Glazer Dermatology, Buffalo Grove, IL, U.S.A
| | - J A Barden
- Biosceptre (Australia) Pty Ltd., 11 Julius Avenue, North Ryde, NSW, 2113, Australia
| | - A Glazer
- Glazer Dermatology, Buffalo Grove, IL, U.S.A
| | - L C Teh
- Biosceptre (Australia) Pty Ltd., 11 Julius Avenue, North Ryde, NSW, 2113, Australia
| | - J King
- Biosceptre (Australia) Pty Ltd., 11 Julius Avenue, North Ryde, NSW, 2113, Australia
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Ferrari D, Malavasi F, Antonioli L. A Purinergic Trail for Metastases. Trends Pharmacol Sci 2016; 38:277-290. [PMID: 27989503 DOI: 10.1016/j.tips.2016.11.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/09/2016] [Accepted: 11/16/2016] [Indexed: 01/14/2023]
Abstract
Nucleotides and nucleosides have emerged as important modulators of tumor biology. Recently acquired evidence shows that, when these molecules are released by cancer cells or surrounding tissues, they act as potent prometastatic factors, favoring tumor cell migration and tissue colonization. Therefore, nucleotides and nucleosides should be considered as a new class of prometastatic factors. In this review, we focus on the prometastatic roles of nucleotides and discuss future applications of purinergic signaling modulation in view of antimetastatic therapies.
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Affiliation(s)
- Davide Ferrari
- Department of Life Science and Biotechnology, University of Ferrara, Ferrara, Italy.
| | - Fabio Malavasi
- Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Torino and Transplant Immunology, Città della Salute e della Scienza, Torino, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Hu J, Ye F, Cui M, Lee P, Wei C, Hao Y, Wang X, Wang Y, Lu Z, Galsky M, McBride R, Wang L, Wang D, Cordon-Cardo C, Wang C, Zhang DY. Protein Profiling of Bladder Urothelial Cell Carcinoma. PLoS One 2016; 11:e0161922. [PMID: 27626805 PMCID: PMC5023150 DOI: 10.1371/journal.pone.0161922] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 08/15/2016] [Indexed: 12/16/2022] Open
Abstract
This study aimed to detect protein changes that can assist to understand the underlying biology of bladder cancer. The data showed forty five proteins were found to be differentially expressed comparing tumors vs non-tumor tissues, of which EGFR and cdc2p34 were correlated with muscle invasion and histological grade. Ten proteins (ß-catenin, HSP70, autotaxin, Notch4, PSTPIP1, DPYD, ODC, cyclinB1, calretinin and EPO) were able to classify muscle invasive BCa (MIBC) into 2 distinct groups, with group 2 associated with poorer survival. Finally, 3 proteins (P2X7, cdc25B and TFIIH p89) were independent factors for favorable overall survival.
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Affiliation(s)
- Jinghai Hu
- Department of Urology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China
| | - Fei Ye
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States of America
| | - Miao Cui
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States of America
| | - Peng Lee
- Departments of Pathology, New York University, School of Medicine, New York, NY, 10010, United States of America
| | - Chengguo Wei
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, 10029, United States of America
| | - Yuanyuan Hao
- Department of Urology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China
| | - Xiaoqing Wang
- Department of Urology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China
| | - Yanbo Wang
- Department of Urology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China
| | - Zhihua Lu
- Department of Urology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China
| | - Matthew Galsky
- Division of Hematology and Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, 10029, United States of America
| | - Russell McBride
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States of America
| | - Li Wang
- Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, 10029, United States of America
| | - Dongwen Wang
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030002, China
| | - Carlos Cordon-Cardo
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States of America
| | - Chunxi Wang
- Department of Urology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China
- * E-mail: (DYZ); (CXW)
| | - David Y. Zhang
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States of America
- * E-mail: (DYZ); (CXW)
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Solini A, Simeon V, Derosa L, Orlandi P, Rossi C, Fontana A, Galli L, Di Desidero T, Fioravanti A, Lucchesi S, Coltelli L, Ginocchi L, Allegrini G, Danesi R, Falcone A, Bocci G. Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients. Oncotarget 2016; 6:28743-54. [PMID: 26337470 PMCID: PMC4745689 DOI: 10.18632/oncotarget.4926] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 08/10/2015] [Indexed: 12/12/2022] Open
Abstract
VEGFR-2 and P2X7 receptor (P2X7R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X7R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94–152.96) and 65.65 months (95% CI, 52.95–76.53) for the favorable and the unfavorable genetic profile, respectively (p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis.
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Affiliation(s)
- Anna Solini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Vittorio Simeon
- Laboratory of Pre-Clinical and Translational Research, IRCCS - CROB Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy
| | - Lisa Derosa
- Oncology Unit 2, University Hospital of Pisa, Pisa, Italy
| | - Paola Orlandi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Rossi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Andrea Fontana
- Oncology Unit 2, University Hospital of Pisa, Pisa, Italy
| | - Luca Galli
- Oncology Unit 2, University Hospital of Pisa, Pisa, Italy
| | - Teresa Di Desidero
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Anna Fioravanti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Sara Lucchesi
- Division of Medical Oncology, Pontedera Hospital, Azienda USL of Pisa, Pontedera, Italy
| | - Luigi Coltelli
- Division of Medical Oncology, Pontedera Hospital, Azienda USL of Pisa, Pontedera, Italy
| | - Laura Ginocchi
- Division of Medical Oncology, Pontedera Hospital, Azienda USL of Pisa, Pontedera, Italy
| | - Giacomo Allegrini
- Division of Medical Oncology, Pontedera Hospital, Azienda USL of Pisa, Pontedera, Italy
| | - Romano Danesi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Guido Bocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Park JH, Williams DR, Lee JH, Lee SD, Lee JH, Ko H, Lee GE, Kim S, Lee JM, Abdelrahman A, Müller CE, Jung DW, Kim YC. Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion. J Med Chem 2016; 59:7410-30. [PMID: 27427902 DOI: 10.1021/acs.jmedchem.5b01690] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The P2X7 receptor (P2X7R) has been reported as a key mediator in inflammatory processes and cancer invasion/metastasis. In this study, we report the discovery of novel P2X7R antagonists and their functional activities as potential antimetastatic agents. Modifications of the hydantoin core-skeleton and the side chain substituents of the P2X7R antagonist 7 were performed. The structure-activity relationships (SAR) and optimization demonstrated the importance of the sulfonyl group at the R1 position and the substituted position and overall size of R2 for P2X7R antagonism. The optimized novel analogues displayed potent P2X7 receptor antagonism (IC50 = 0.11-112 nM) along with significant suppressive effects on IL-1β release (IC50 = 0.32-210 nM). Moreover, representative antagonists (12g, 13k, and 17d) with imidazole and uracil core skeletons significantly inhibited the invasion of MDA-MB-231 triple negative breast cancer cells and cancer cell migration in a zebrafish xenograft model, suggesting the potential therapeutic application of these novel P2X7 antagonists to block metastatic cancer.
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Affiliation(s)
- Jin-Hee Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Darren R Williams
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Ji-Hyung Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - So-Deok Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Je-Heon Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Hyojin Ko
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Ga-Eun Lee
- Department of Pharmaceutical Industry, Korea Health Industry Development Institute (KHIDI) , Chungcheongbuk-do 363-700, Republic of Korea
| | - Sujin Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Jeong-Min Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Aliaa Abdelrahman
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany
| | - Christa E Müller
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany
| | - Da-Woon Jung
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
| | - Yong-Chul Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.,Department of Medical System Engineering, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea
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Schmid S, Kübler M, Korcan Ayata C, Lazar Z, Haager B, Hoßfeld M, Meyer A, Cicko S, Elze M, Wiesemann S, Zissel G, Passlick B, Idzko M. Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer. Lung Cancer 2015; 90:516-21. [PMID: 26505137 DOI: 10.1016/j.lungcan.2015.10.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 09/13/2015] [Accepted: 10/04/2015] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Purines are well-known as intracellular sources for energy but they also act as extracellular signaling molecules. In the recent years, there has been a growing interest in the therapeutic potential of purinergic signaling for cancer treatment. This is the first study to analyze lung purine levels and purinergic receptors in non-small-cell lung cancer (NSCLC) patients. MATERIALS AND METHODS In this prospective clinical trial we enrolled 26 patients with NSCLC and 21 patients with chronic obstructive pulmonary disease (COPD) without signs of malignancy. The purine concentrations were analyzed in bronchoalveolar lavage fluid (BALF) using fluorescent/luminescent assays. Expression of purinergic receptors and ectonucleotidases were analyzed using real time quantitative polymerase chain reaction (RT-qPCR). RESULTS Patients with NSCLC have significantly lower ATP and ADP concentrations in BALF than patients with COPD (p=0.006 and p=0.009). Expression of the ectonucleotidase CD39 is significantly higher in BAL cells from cancer patients compared to COPD (p=0.001) as well as in metastasized tumors compared to non-metastasized tumors (p=0.009). Receptor-analysis revealed a higher expression of P2X4 (p=0.03), P2X7 (p=0.001) and P2Y1 (p=0.003) in BAL cells of tumors with distant metastasis. CONCLUSION Our data suggests a role for CD39 in lung cancer tumor microenvironment, influencing tumor invasiveness and metastasization. Potentially the increased degradation of ATP and ADP leads to a subversion of their anti-neoplastic effects. Furthermore P2Y1, P2X4 and P2X7 receptors are upregulated in BAL cells in metastatic disease. Our findings might facilitate the identification of new therapeutic targets for cancer immunotherapy.
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Affiliation(s)
- Severin Schmid
- University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany.
| | - Markus Kübler
- University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany
| | - C Korcan Ayata
- University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany
| | - Zsofia Lazar
- Semmelweis University, Department of Pneumology, Budapest, Hungary
| | - Benedikt Haager
- University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany
| | - Madelon Hoßfeld
- University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany
| | - Anja Meyer
- University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany
| | - Sanja Cicko
- University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany
| | - Mirjam Elze
- University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany
| | - Sebastian Wiesemann
- University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany
| | - Gernot Zissel
- University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany
| | - Bernward Passlick
- University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany
| | - Marco Idzko
- University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany
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50
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Svennersten K, Hallén-Grufman K, de Verdier PJ, Wiklund NP, Poljakovic M. Localization of P2X receptor subtypes 2, 3 and 7 in human urinary bladder. BMC Urol 2015; 15:81. [PMID: 26253104 PMCID: PMC4529706 DOI: 10.1186/s12894-015-0075-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 07/28/2015] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Voiding dysfunctions are a common problem that has a severe negative impact on the quality of life. Today there is a need for new drug targets for these conditions. The role of ATP receptors in bladder physiology has been studied for some time, primarily in animal models. The aim of this work is to investigate the localization of the ATP receptors P2X2, P2X3 and P2X7 and their colocalization with vimentin and actin in the human urinary bladder. METHODS Immunohistochemical analysis was conducted on full-thickness bladder tissues from fundus and trigonum collected from 15 patients undergoing open radical cystectomy due to chronic cystitis, bladder cancer or locally advanced prostate cancer. Colocalization analyses were performed between the three different P2X subtypes and the structural proteins vimentin and actin. Specimens were examined using epifluorescence microscopy and correlation coefficients were calculated for each costaining as well as the mean distance from the laminin positive basal side of the urothelium to the vimentin positive cells located in the suburothelium. RESULTS P2X2 was expressed in vimentin positive cells located in the suburothelium. Less distinct labelling of P2X2 was also observed in actin positive smooth muscle cells and in the urothelium. P2X3 was expressed in vimentin positive cells surrounding the smooth muscle, and in vimentin positive cells located in the suburothelium. Weaker P2X3 labelling was seen in the urothelium. P2X7 was expressed in the smooth muscle cells and the urothelium. In the suburothelium, cells double positive for P2X2 and vimentin where located closer to the urothelium while cells double positive for P2X3 and vimentin where located further from the urothelium. CONCLUSION The results from this study demonstrate that there is a significant difference in the expression of the purinergic P2X2, P2X3 and P2X7 receptors in the different histological layers of the human urinary bladder.
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Affiliation(s)
- Karl Svennersten
- Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, 171 76, Stockholm, Sweden.
- Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
| | - Katarina Hallén-Grufman
- Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, 171 76, Stockholm, Sweden.
- Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
| | - Petra J de Verdier
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - N Peter Wiklund
- Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, 171 76, Stockholm, Sweden.
- Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
| | - Mirjana Poljakovic
- Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, 171 76, Stockholm, Sweden.
- Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
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