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Nie XH, Li TZ, Peng CM. ATP ion channel-type P2X purinergic receptors as a key regulatory molecule in breast cancer progression. Pathol Res Pract 2025; 267:155844. [PMID: 39965402 DOI: 10.1016/j.prp.2025.155844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/31/2025] [Accepted: 02/13/2025] [Indexed: 02/20/2025]
Abstract
Studies have confirmed that ATP ion channel P2X purinergic receptors play a key role in tumor growth and metastasis. Similarly, P2X purinergic receptors can be used as a favorable regulatory molecule of breast cancer cells to participate in the progression of breast cancer. There are abundant ATP and its cleavage products in breast cancer microenvironment, which can be used as natural activators of P2X purinergic receptors. P2X purinergic receptors play a role in regulating the growth and metastasis of breast cancer cells by mediating signal transduction, growth regulation and immune cell activity in microenvironment. However, the application of P2X purinergic receptors antagonist has the pharmacological characteristics of inhibiting the progression of breast cancer cells. Among P2X purinergic receptors, there is a close relationship between P2X7 receptor and breast cancer patients. P2X purinergic receptors can be used as a biological marker for breast cancer patients. In this paper, we discuss the functional role and regulatory molecular mechanism of P2X purinergic receptors in the progression of breast cancer. The pharmacological effects of P2X purinergic receptors selective antagonist on the growth, metastasis and invasion of breast cancer cells were further discussed. Therefore, P2X purinergic receptors can be used as a key regulatory molecule of breast cancer and a pharmacological target for potential therapy.
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Affiliation(s)
- Xin-Hua Nie
- Department of Gastroenterology, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Teng-Zheng Li
- Department of Gastroenterology, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Cheng-Ming Peng
- Department of Gastroenterology, The second affiliated hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China.
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Kiaie SH, Zangi AR, Sheibani M, Hemmati S, Baradaran B, Valizadeh H. Novel synthesized ionizable lipid for LNP-mediated P2X7siRNA to inhibit migration and induce apoptosis of breast cancer cells. Purinergic Signal 2024; 20:533-546. [PMID: 38436880 PMCID: PMC11377399 DOI: 10.1007/s11302-024-09989-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 01/23/2024] [Indexed: 03/05/2024] Open
Abstract
The development of ionizable lipid (IL) was necessary to enable the effective formulation of small interfering RNA (siRNA) to inhibit P2X7 receptors (P2X7R), a key player in tumor proliferation, apoptosis, and metastasis. In this way, the synthesis and utility of IL for enhancing cellular uptake of lipid nanoparticles (LNP) improve the proper delivery of siRNA-LNPs for knockdown overexpression of P2X7R. Therefore, to evaluate the impact of P2X7 knockdown on breast cancer (BC) migration and apoptosis, a branched and synthesized ionizable lipid (SIL) was performed for efficient transfection of LNP with siRNA for targeting P2X7 receptors (siP2X7) in mouse 4T-1 cells. Following synthesis and structural analysis of SIL, excellent characterization of the LNP was achieved (Z-average 126.8 nm, zeta-potential - 12.33, PDI 0.16, and encapsulation efficiency 85.35%). Afterward, the stability of the LNP was evaluated through an analysis of the leftover composition, and toxic concentration values for SIL and siP2X7 were determined. Furthermore, siP2X7-LNP cellular uptake in the formulation was assessed via confocal microscopy. Following determining the optimal dose (45 pmol), wound healing analysis was assessed using scratch assay microscopy, and apoptosis was evaluated using flow cytometry. The use of the innovative branched SIL in the formulation of siP2X7-LNP resulted in significant inhibition of migration and induction of apoptosis in 4T-1 cells due to improved cellular uptake. Subsequently, the innovative SIL represents a critical role in efficiently delivering siRNA against murine triple-negative breast cancer cells (TNBC) using LNP formulation, resulting in significant efficacy.
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Affiliation(s)
- Seyed Hossein Kiaie
- Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Rajabi Zangi
- Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sheibani
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Razi Drug Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Salar Hemmati
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center and School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hadi Valizadeh
- Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
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Kiaie SH, Hatami Z, Nasr MS, Pazooki P, Hemmati S, Baradaran B, Valizadeh H. Pharmacological interaction and immune response of purinergic receptors in therapeutic modulation. Purinergic Signal 2024; 20:321-343. [PMID: 37843749 PMCID: PMC11303644 DOI: 10.1007/s11302-023-09966-7] [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: 05/12/2023] [Accepted: 09/10/2023] [Indexed: 10/17/2023] Open
Abstract
Nucleosides and purine nucleotides serve as transmitter and modulator agents that extend their functions beyond the cell. In this context, purinergic signaling plays a crucial role in regulating energy homeostasis and modulating metabolic alterations in tumor cells. Therefore, it is essential to consider the pharmacological targeting of purinergic receptors (PUR), which encompass the expression and inhibition of P1 receptors (metabotropic adenosine receptors) as well as P2 receptors (extracellular ATP/ADP) comprising P2X and P2Y receptors. Thus, the pharmacological interaction between inhibitors (such as RNA, monoclonal antibodies, and small molecules) and PUR represents a key aspect in facilitating the development of therapeutic interventions. Moreover, this review explores recent advancements in pharmacological inhibitors and the regulation of innate and adaptive immunity of PUR, specifically in relation to immunological and inflammatory responses. These responses encompass the release of pro-inflammatory cytokines (PIC), the production of reactive oxygen and nitrogen species (ROS and RNS), the regulation of T cells, and the activation of inflammasomes in all human leukocytes.
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Affiliation(s)
- Seyed Hossein Kiaie
- Drug Applied Research Center, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Hatami
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Sadegh Nasr
- Department of Computer Science and Engineering Multi-Interprofessional Center for Health Informatics (MICHI), The University of Texas at Arlington, Arlington, TX, USA
| | - Pouya Pazooki
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salar Hemmati
- Institute Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hadi Valizadeh
- Drug Applied Research Center, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
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Mull ML, Pratt SJP, Thompson KN, Annis DA, Gad AA, Lee RM, Chang KT, Stemberger MB, Ju JA, Gilchrist DE, Boyman L, Vitolo MI, Lederer WJ, Martin SS. Disruption of P2Y2 signaling promotes breast tumor cell dissemination by reducing ATP-dependent calcium elevation and actin localization to cell junctions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.03.31.533191. [PMID: 37034765 PMCID: PMC10081304 DOI: 10.1101/2023.03.31.533191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
The tumor microenvironment and wound healing after injury both contain extremely high concentrations of the extracellular signaling molecule, adenosine triphosphate (ATP) compared to normal tissue. P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neurological cell signaling. Here we report its role and importance in breast epithelial cell signaling and how it is altered in metastatic breast cancer. In response to ATP activation, P2Y2 receptor signaling causes an increase of intracellular Ca 2+ in non-tumorigenic breast epithelial cells, while their tumorigenic and metastatic counterparts have significantly reduced Ca 2+ responses. The non-tumorigenic cells respond to increased Ca 2+ with actin polymerization and localization to cell edges, while the metastatic cells remained unaffected. The increase in intracellular Ca 2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization and caused cell dissemination from spheroids in non-tumorigenic breast epithelial cells. Furthermore, the lack of Ca 2+ concentration changes and actin mobilization in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates rapid changes that occur after elevated intracellular Ca 2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response.
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Liu C, Wang X, Wang S, Xiang J, Xie H, Tan Z, Li X, Zhang J, Dong W. Comprehensive analysis of P2Y family genes expression, immune characteristics, and prognosis in pan-cancer. Transl Oncol 2023; 37:101776. [PMID: 37672858 PMCID: PMC10485639 DOI: 10.1016/j.tranon.2023.101776] [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: 03/28/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND P2Y receptors are a family of G protein-coupled receptor genes that have an important function in cancer development and metastasis. However, systematic studies have not been conducted on human tumors. This study attempted to explore the role of P2Y family genes (P2Ys) in pan-cancer. METHODS Gene expression and clinical data were downloaded from The Cancer Genome Alas dataset. Gene differential expression, mutation, prognosis, tumor microenvironment (TME) (containing immune cells infiltration, Estimate/immune/stromal scores, immune checkpoints, immune and molecular subtypes, DNA repair genes and methyltransferase), clinical correlation, protein-protein interaction network and functional enrichment analysis were performed. In addition, experiments such as western blots were performed for validation. RESULTS Eight P2Ys were differentially expressed in most tumor and normal tissues, and their abnormal expression in a variety of cancers could significantly reduce the survival rate of patients. Expression levels of P2Ys, especially P2Y6, P2Y12, P2Y13, P2Y14, were correlated significantly with immune cells, immune checkpoint genes, immune and molecular subtypes and Estimate/immune/stromal scores in a variety of cancers such as uveal melanoma, liver hepatocellular carcinoma, stomach adenocarcinoma, colorectal cancer (CRC), prostate adenocarcinoma, breast invasive carcinoma and uterine corpus endometrial carcinoma (all p < 0.05). P2Ys play an important role in TME and are involved in immune regulation. In addition, enrichment analysis and western blots showed that the levels of P2Y2 and P2Y6 expression regulate the Akt/GSK-3β/β-catenin pathway in CRC, thereby affecting epithelial-to-mesenchymal transition. CONCLUSION P2Ys may be used as potential pan-cancer biomarkers in prognosis and immunology. They may also be new targets for tumor immunotherapy, which has wide clinical implications.
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Affiliation(s)
- Chuan Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xiaoli Wang
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Siwei Wang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jiankang Xiang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Huabing Xie
- Department of General Practice, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zongbiao Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xinshu Li
- Department of Clinical Medicine, Xi'an Medical of University, Xi'an 710068, China
| | - Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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Singh J, Meena A, Luqman S. New frontiers in the design and discovery of therapeutics that target calcium ion signaling: a novel approach in the fight against cancer. Expert Opin Drug Discov 2023; 18:1379-1392. [PMID: 37655549 DOI: 10.1080/17460441.2023.2251887] [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: 05/15/2023] [Accepted: 08/22/2023] [Indexed: 09/02/2023]
Abstract
INTRODUCTION The Ca2+ signaling toolkit is currently under investigation as a potential target for addressing the threat of cancer. A growing body of evidence suggests that calcium signaling plays a crucial role in promoting various aspects of cancer, including cell proliferation, progression, drug resistance, and migration-related activities. Consequently, focusing on these altered Ca2+ transporting proteins has emerged as a promising area of research for cancer treatment. AREAS COVERED This review highlights the existing research on the role of Ca2+-transporting proteins in cancer progression. It discusses the current studies evaluating Ca2+ channel/transporter/pump blockers, inhibitors, or regulators as potential anticancer drugs. Additionally, the review addresses specific gaps in our understanding of the field that may require further investigation. EXPERT OPINION Targeting specific Ca2+ signaling cascades could disrupt normal cellular activities, making cancer therapy complex and elusive. Therefore, there is a need for improvements in current Ca2+ signaling pathway focused medicines. While synthetic molecules and plant compounds show promise, they also come with certain limitations. Hence, exploring the framework of targeted drug delivery, structure-rationale-based designing, and repurposing potential drugs to target Ca2+ transporting proteins could potentially lead to a significant breakthrough in cancer treatment.
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Affiliation(s)
- Jyoti Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Pinto-Cardoso R, Bessa-Andrês C, Correia-de-Sá P, Bernardo Noronha-Matos J. Could hypoxia rehabilitate the osteochondral diseased interface? Lessons from the interplay of hypoxia and purinergic signals elsewhere. Biochem Pharmacol 2023:115646. [PMID: 37321413 DOI: 10.1016/j.bcp.2023.115646] [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: 04/07/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023]
Abstract
The osteochondral unit comprises the articular cartilage (90%), subchondral bone (5%) and calcified cartilage (5%). All cells present at the osteochondral unit that is ultimately responsible for matrix production and osteochondral homeostasis, such as chondrocytes, osteoblasts, osteoclasts and osteocytes, can release adenine and/or uracil nucleotides to the local microenvironment. Nucleotides are released by these cells either constitutively or upon plasma membrane damage, mechanical stress or hypoxia conditions. Once in the extracellular space, endogenously released nucleotides can activate membrane-bound purinoceptors. Activation of these receptors is fine-tuning regulated by nucleotides' breakdown by enzymes of the ecto-nucleotidase cascade. Depending on the pathophysiological conditions, both the avascular cartilage and the subchondral bone subsist to significant changes in oxygen tension, which has a tremendous impact on tissue homeostasis. Cell stress due to hypoxic conditions directly influences the expression and activity of several purinergic signalling players, namely nucleotide release channels (e.g. Cx43), NTPDase enzymes and purinoceptors. This review gathers experimental evidence concerning the interplay between hypoxia and the purinergic signalling cascade contributing to osteochondral unit homeostasis. Reporting deviations to this relationship resulting from pathological alterations of articular joints may ultimately unravel novel therapeutic targets for osteochondral rehabilitation. At this point, one can only hypothesize how hypoxia mimetic conditions can be beneficial to the ex vivo expansion and differentiation of osteo- and chondro-progenitors for auto-transplantation and tissue regenerative purposes.
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Affiliation(s)
- Rui Pinto-Cardoso
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - Catarina Bessa-Andrês
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - Paulo Correia-de-Sá
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - José Bernardo Noronha-Matos
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP).
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Nasimi Shad A, Fanoodi A, Maharati A, Akhlaghipour I, Moghbeli M. Molecular mechanisms of microRNA-301a during tumor progression and metastasis. Pathol Res Pract 2023; 247:154538. [PMID: 37209575 DOI: 10.1016/j.prp.2023.154538] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/10/2023] [Accepted: 05/16/2023] [Indexed: 05/22/2023]
Abstract
Cancer is known as one of the leading causes of human deaths globally. Late diagnosis is considered as one of the main reasons for the high mortality rate among cancer patients. Therefore, the introduction of early diagnostic tumor markers can improve the efficiency of therapeutic modalities. MicroRNAs (miRNAs) have a key role in regulation of cell proliferation and apoptosis. MiRNAs deregulation has been frequently reported during tumor progressions. Since, miRNAs have a high stability in body fluids; they can be used as the reliable non-invasive tumor markers. Here, we discussed the role of miR-301a during tumor progressions. MiR-301a mainly functions as an oncogene via the modulation of transcription factors, autophagy, epithelial-mesenchymal transition (EMT), and signaling pathways. This review paves the way to suggest miR-301a as a non-invasive marker for the early tumor diagnosis. MiR-301a can also be suggested as an effective target in cancer therapy.
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Affiliation(s)
- Arya Nasimi Shad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Fanoodi
- Student Research Committee, Faculty of Medicine, Birjand University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Janke EK, Chalmers SB, Roberts-Thomson SJ, Monteith GR. Intersection between calcium signalling and epithelial-mesenchymal plasticity in the context of cancer. Cell Calcium 2023; 112:102741. [PMID: 37060674 DOI: 10.1016/j.ceca.2023.102741] [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: 02/19/2023] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/17/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a form of cellular phenotypic plasticity and is considered a crucial step in the progression of many cancers. The calcium ion (Ca2+) acts as a ubiquitous second messenger and is implicated in many cellular processes, including cell death, migration, invasion and more recently EMT. Throughout this review, the complex interplay between Ca2+ signalling and EMT will be explored. An overview of the Ca2+ pathways that are remodelled as a consequence of EMT is provided and the role of Ca2+ signalling in regulating EMT and its significance is considered. Ca2+ signalling pathways may represent a therapeutic opportunity to regulate EMT. However, as will be described in this review, the complexity of these signalling pathways represents significant challenges that must be considered if Ca2+ signalling is to be manipulated with the aim of therapeutic intervention in cancer.
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Affiliation(s)
- Ellen K Janke
- School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Brisbane, Queensland, 4102, Australia
| | - Silke B Chalmers
- Department of Biomedicine, Aarhus University, Nordre Ringgade 1, Aarhus C, 8000, Denmark
| | - Sarah J Roberts-Thomson
- School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Brisbane, Queensland, 4102, Australia
| | - Gregory R Monteith
- School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Brisbane, Queensland, 4102, Australia.
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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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Sheng G, Gao Y, Ding Q, Zhang R, Wang T, Jing S, Zhao H, Ma T, Wu H, Yang Y. P2RX7 promotes osteosarcoma progression and glucose metabolism by enhancing c-Myc stabilization. J Transl Med 2023; 21:132. [PMID: 36803784 PMCID: PMC9940387 DOI: 10.1186/s12967-023-03985-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/13/2023] [Indexed: 02/22/2023] Open
Abstract
BACKGROUND Osteosarcoma is the most common malignant tumor in bone and its prognosis has reached a plateau in the past few decades. Recently, metabolic reprogramming has attracted increasing attention in the field of cancer research. In our previous study, P2RX7 has been identified as an oncogene in osteosarcoma. However, whether and how P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming remains unexplored. METHODS We used CRISPR/Cas9 genome editing technology to establish P2RX7 knockout cell lines. Transcriptomics and metabolomics were performed to explore metabolic reprogramming in osteosarcoma. RT-PCR, western blot and immunofluorescence analyses were used to determine gene expression related to glucose metabolism. Cell cycle and apoptosis were examined by flowcytometry. The capacity of glycolysis and oxidative phosphorylation were assessed by seahorse experiments. PET/CT was carried out to assess glucose uptake in vivo. RESULTS We demonstrated that P2RX7 significantly promotes glucose metabolism in osteosarcoma via upregulating the expression of genes related to glucose metabolism. Inhibition of glucose metabolism largely abolishes the ability of P2RX7 to promote osteosarcoma progression. Mechanistically, P2RX7 enhances c-Myc stabilization by facilitating nuclear retention and reducing ubiquitination-dependent degradation. Furthermore, P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming in a predominantly c-Myc-dependent manner. CONCLUSIONS P2RX7 plays a key role in metabolic reprogramming and osteosarcoma progression via increasing c-Myc stability. These findings provide new evidence that P2RX7 might be a potential diagnostic and/or therapeutic target for osteosarcoma. Novel therapeutic strategies targeting metabolic reprogramming appear to hold promise for a breakthrough in the treatment of osteosarcoma.
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Affiliation(s)
- Gaohong Sheng
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Yuan Gao
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qing Ding
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Ruizhuo Zhang
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Tianqi Wang
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Shaoze Jing
- grid.470966.aShanxi Bethune Hospital, Tongji Shanxi Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032 China
| | - Hongqi Zhao
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Tian Ma
- grid.412793.a0000 0004 1799 5032Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030 China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China.
| | - Yong Yang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China.
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Wang X, Zhao B, Ren D, Hu X, Qiao J, Zhang D, Zhang Y, Pan Y, Fan Y, Liu L, Wang X, Ma H, Jia X, Song S, Zhao C, Liu J, Wang L. Pyrimidinergic receptor P2Y6 expression is elevated in lung adenocarcinoma and is associated with poor prognosis. Cancer Biomark 2023; 38:191-201. [PMID: 37545227 DOI: 10.3233/cbm-230137] [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] [Indexed: 08/08/2023]
Abstract
BACKGROUD Previous in vitro studies have indicated that pyrimidinergic receptor P2Y6 (P2RY6, P2Y6 receptor) may function as a cancer-promoting factor in lung adenocarcinoma (LUAD). However, the prognostic significance of P2RY6 expression in LUAD has not been investigated. OBJECTIVE This study aimed to assess the impact of P2RY6 expression on the survival of patients with LUAD. METHODS First, we assessed P2RY6 mRNA and protein expression in LUAD and non-cancerous lung tissues using the online bioinformatics analysis tool GEPIA, fresh LUAD tissues, and LUAD tissue microarrays (TMAs). Second, we investigated the correlation between P2RY6 expression and clinicopathological parameters of LUAD patients based on data from The Cancer Genome Atlas (TCGA) database and TMAs. Finally, we analyzed the prognostic significance of P2RY6 expression in LUAD using the online survival analysis tool Kaplan-Meier Plotter and data from TMAs. RESULTS We demonstrated that P2RY6 mRNA and protein expression levels in LUAD tissues were significantly higher than those in non-cancerous lung tissues. The expression of P2RY6 in LUAD was positively correlated with poor differentiation, more lymph node metastasis, and more advanced clinical stage. Higher P2RY6 expression level was correlated with shorter survival of the LUAD patients. Univariate and multivariate Cox regression analyses indicated that higher P2RY6 tumor expression was an independent unfavorable prognostic factor for LUAD patients. CONCLUSIONS P2RY6 expression was elevated in LUAD and correlated with poor prognosis.
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Affiliation(s)
- Xiuli Wang
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Baoshan Zhao
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Dan Ren
- Department of Pathology, Daqing Longnan Hospital, Daqing, Heilongjiang, China
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Xiaolei Hu
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Juanjuan Qiao
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Dongmei Zhang
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Yanzhi Zhang
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Yu Pan
- Department of Anatomy, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Yuhua Fan
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Lili Liu
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Xiaoxue Wang
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Huanhuan Ma
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Xueling Jia
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Sihang Song
- Department of Histology and Embryology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Chong Zhao
- Library of Harbin Medical University-Daqing, Daqing, Heilongjiang, China
| | - Jingbo Liu
- Department of Pathology, Daqing Longnan Hospital, Daqing, Heilongjiang, China
| | - Lin Wang
- Department of Pathology and Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China
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13
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Scarpellino G, Genova T, Quarta E, Distasi C, Dionisi M, Fiorio Pla A, Munaron L. P2X Purinergic Receptors Are Multisensory Detectors for Micro-Environmental Stimuli That Control Migration of Tumoral Endothelium. Cancers (Basel) 2022; 14:2743. [PMID: 35681724 PMCID: PMC9179260 DOI: 10.3390/cancers14112743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 05/30/2022] [Indexed: 02/04/2023] Open
Abstract
The tumoral microenvironment often displays peculiar features, including accumulation of extracellular ATP, hypoxia, low pH-acidosis, as well as an imbalance in zinc (Zn2+) and calcium (Ca2+). We previously reported the ability of some purinergic agonists to exert an anti-migratory activity on tumor-derived human endothelial cells (TEC) only when applied at a high concentration. They also trigger calcium signals associated with release from intracellular stores and calcium entry from the external medium. Here, we provide evidence that high concentrations of BzATP (100 µM), a potent agonist of P2X receptors, decrease migration in TEC from different tumors, but not in normal microvascular ECs (HMEC). The same agonist evokes a calcium increase in TEC from the breast and kidney, as well as in HMEC, but not in TEC from the prostate, suggesting that the intracellular pathways responsible for the P2X-induced impairment of TEC migration could vary among different tumors. The calcium signal is mainly due to a long-lasting calcium entry from outside and is strictly dependent on the presence of the receptor occupancy. Low pH, as well as high extracellular Zn2+ and Ca2+, interfere with the response, a distinctive feature typically found in some P2X purinergic receptors. This study reveals that a BzATP-sensitive pathway impairs the migration of endothelial cells from different tumors through mechanisms finely tuned by environmental factors.
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Affiliation(s)
- Giorgia Scarpellino
- Department of Life Sciences & Systems Biology, University of Torino, 10123 Torino, Italy; (G.S.); (T.G.); (E.Q.); (A.F.P.)
| | - Tullio Genova
- Department of Life Sciences & Systems Biology, University of Torino, 10123 Torino, Italy; (G.S.); (T.G.); (E.Q.); (A.F.P.)
| | - Elisa Quarta
- Department of Life Sciences & Systems Biology, University of Torino, 10123 Torino, Italy; (G.S.); (T.G.); (E.Q.); (A.F.P.)
| | - Carla Distasi
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.D.); (M.D.)
| | - Marianna Dionisi
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.D.); (M.D.)
| | - Alessandra Fiorio Pla
- Department of Life Sciences & Systems Biology, University of Torino, 10123 Torino, Italy; (G.S.); (T.G.); (E.Q.); (A.F.P.)
| | - Luca Munaron
- Department of Life Sciences & Systems Biology, University of Torino, 10123 Torino, Italy; (G.S.); (T.G.); (E.Q.); (A.F.P.)
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14
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Rao R, Shah S, Bhattacharya D, Toukam DK, Cáceres R, Pomeranz Krummel DA, Sengupta S. Ligand-Gated Ion Channels as Targets for Treatment and Management of Cancers. Front Physiol 2022; 13:839437. [PMID: 35350689 PMCID: PMC8957973 DOI: 10.3389/fphys.2022.839437] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/07/2022] [Indexed: 12/24/2022] Open
Abstract
Ligand-gated ion channels are an ionotropic receptor subtype characterized by the binding of an extracellular ligand, followed by the transient passage of ions through a transmembrane pore. Ligand-gated ion channels are commonly subcategorized into three superfamilies: purinoreceptors, glutamate receptors, and Cys-loop receptors. This classification is based on the differing topographical morphology of the receptors, which in turn confers functional differences. Ligand-gated ion channels have a diverse spatial and temporal expression which implicate them in key cellular processes. Given that the transcellular electrochemical gradient is finely tuned in eukaryotic cells, any disruption in this homeostasis can contribute to aberrancies, including altering the activity of pro-tumorigenic molecular pathways, such as the MAPK/ERK, RAS, and mTOR pathways. Ligand-gated ion channels therefore serve as a potential targetable system for cancer therapeutics. In this review, we analyze the role that each of the three ligand-gated ion channel superfamilies has concerning tumor proliferation and as a target for the treatment of cancer symptomatology.
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Affiliation(s)
| | | | | | | | | | - Daniel A. Pomeranz Krummel
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Soma Sengupta
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, United States
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15
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Yue Y, Zhang Q, Sun Z. CX3CR1 Acts as a Protective Biomarker in the Tumor Microenvironment of Colorectal Cancer. Front Immunol 2022; 12:758040. [PMID: 35140706 PMCID: PMC8818863 DOI: 10.3389/fimmu.2021.758040] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment (TME) plays an important role in the pathogenesis of many cancers. We aimed to screen the TME-related hub genes of colorectal adenoma (CRAD) and identify possible prognostic biomarkers. The gene expression profiles and clinical data of 464 CRAD patients in The Cancer Genome Atlas (TCGA) database were downloaded. The Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was performed to calculate the ImmuneScore, StromalScore, and EstimateScore. Thereafter, differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein–protein interaction (PPI) analysis were performed to explore the roles of DEGs. Furthermore, univariate and multivariate Cox analyses were accomplished to identify independent prognostic factors of CRAD. CX3CR1 was selected as a hub gene, and the expression was confirmed in colorectal cancer (CRC) patients and cell lines. The correlations between CX3CR1 and tumor-infiltrating immune cells were estimated by Tumor IMmune Estimation Resource database (TIMER) and CIBERSORT analysis. Besides, we investigated the effects of coculture with THP-1-derived macrophages with HCT8 cells with low CX3CR1 expression on immune marker expression, cell viability, and migration. There were significant differences in the ImmuneScore and EstimateScore among different stages. Patients with low scores presented significantly lower lifetimes than those in the high-score group. Moreover, we recognized 1,578 intersection genes in ImmuneScore and StromalScore, and these genes were mainly enriched in numerous immune-related biological processes. CX3CR1 was found to be associated with immune cell infiltration levels, immune marker expression, and macrophage polarization. Simultaneous silencing of CX3CR1 and coculture with THP-1 cells further regulated macrophage polarization and promoted the cell proliferation and migration of CRC cells. CX3CR1 was decreased in CRAD tissues and cell lines and was related to T and N stages, tumor differentiation, and prognosis. Our results suggest that CX3CR1 contributes to the recruitment and regulation of immune-infiltrating cells and macrophage polarization in CRC and TAM-induced CRC progression. CX3CR1 may act as a prognostic biomarker in CRC.
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Affiliation(s)
- Yuanyi Yue
- Department of Gastroenterology Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qiang Zhang
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhengrong Sun
- BioBank, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Zhengrong Sun,
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16
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Alvarez CL, Troncoso MF, Espelt MV. Extracellular ATP and adenosine in tumor microenvironment: Roles in epithelial-mesenchymal transition, cell migration, and invasion. J Cell Physiol 2021; 237:389-400. [PMID: 34514618 DOI: 10.1002/jcp.30580] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/11/2022]
Abstract
Under nonpathological conditions, the extracellular nucleotide concentration remains constant and low (nM range) because of a close balance between ATP release and ATP consumption. This balance is completely altered in cancer disease. Adenine and uridine nucleotides are found in the extracellular space of tumors in high millimolar (mM) concentrations acting as extracellular signaling molecules. In general, although uridine nucleotides may be involved in different tumor cell responses, purinergic signaling in cancer is preferentially focused on adenine nucleotides and nucleosides. Extracellular ATP can bind to specific receptors (P receptors) triggering different responses, or it can be hydrolyzed by ectoenzymes bound to cell membranes to render the final product adenosine. The latter pathway plays an important role in the increase of adenosine in tumor microenvironment. In this study, we will focus on extracellular ATP and adenosine, their effects acting as ligands of specific receptors, activating ectoenzymes, and promoting epithelial-mesenchymal transition, migration, and invasion in cancer cells. Finding the roles that these nucleotides play in tumor microenvironment may be important to design new intervention strategies in cancer therapies.
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Affiliation(s)
- Cora L Alvarez
- Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Universidad de Buenos Aires, Buenos Aires, Argentina.,CONICET-Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB) "Prof. Alejandro C. Paladini", Buenos Aires, Argentina
| | - María F Troncoso
- CONICET-Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB) "Prof. Alejandro C. Paladini", Buenos Aires, Argentina.,Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María V Espelt
- CONICET-Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB) "Prof. Alejandro C. Paladini", Buenos Aires, Argentina.,Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
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17
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Sharma A, Ramena GT, Elble RC. Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy. Biomedicines 2021; 9:1077. [PMID: 34572262 PMCID: PMC8466575 DOI: 10.3390/biomedicines9091077] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/15/2021] [Accepted: 07/18/2021] [Indexed: 02/07/2023] Open
Abstract
Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them to signaling hubs needing the cations. Ca2+ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca2+ repositories. Cellular Ca2+ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca2+ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca2+ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca2+ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area.
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Affiliation(s)
- Aarushi Sharma
- Department of Pharmacology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
| | - Grace T. Ramena
- Department of Aquaculture, University of Arkansas, Pine Bluff, AR 71601, USA;
| | - Randolph C. Elble
- Department of Pharmacology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
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18
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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: 29] [Impact Index Per Article: 7.3] [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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19
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Lee D, Hong JH. Ca 2+ Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer. Cancers (Basel) 2021; 13:1473. [PMID: 33806911 PMCID: PMC8004807 DOI: 10.3390/cancers13061473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 01/06/2023] Open
Abstract
Metastatic features of breast cancer in the brain are considered a common pathology in female patients with late-stage breast cancer. Ca2+ signaling and the overexpression pattern of Ca2+ channels have been regarded as oncogenic markers of breast cancer. In other words, breast tumor development can be mediated by inhibiting Ca2+ channels. Although the therapeutic potential of inhibiting Ca2+ channels against breast cancer has been demonstrated, the relationship between breast cancer metastasis and Ca2+ channels is not yet understood. Thus, we focused on the metastatic features of breast cancer and summarized the basic mechanisms of Ca2+-related proteins and channels during the stages of metastatic breast cancer by evaluating Ca2+ signaling. In particular, we highlighted the metastasis of breast tumors to the brain. Thus, modulating Ca2+ channels with Ca2+ channel inhibitors and combined applications will advance treatment strategies for breast cancer metastasis to the brain.
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Affiliation(s)
| | - Jeong Hee Hong
- Department of Health Sciences and Technology, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Korea;
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20
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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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21
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Targeting the purinergic pathway in breast cancer and its therapeutic applications. Purinergic Signal 2021; 17:179-200. [PMID: 33576905 PMCID: PMC7879595 DOI: 10.1007/s11302-020-09760-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 12/06/2020] [Indexed: 12/21/2022] Open
Abstract
Breast cancer (BC) is the most frequent cause of death among women, representing a global public health problem. Here, we aimed to discuss the correlation between the purinergic system and BC, recognizing therapeutic targets. For this, we analyzed the interaction of extracellular nucleotides and nucleosides with the purinergic receptors P1 and P2, as well as the influence of ectonucleotidase enzymes (CD39 and CD73) on tumor progression. A comprehensive bibliographic search was carried out. The relevant articles for this review were found in the PubMed, Scielo, Lilacs, and ScienceDirect databases. It was observed that among the P1 receptors, the A1, A2A, and A2B receptors are involved in the proliferation and invasion of BC, while the A3 receptor is related to the inhibition of tumor growth. Among the P2 receptors, the P2X7 has a dual function. When activated for a short time, it promotes metastasis, but when activated for long periods, it is related to BC cell death. P2Y2 and P2Y6 receptors are related to BC proliferation and invasiveness. Also, the high expression of CD39 and CD73 in BC is strongly related to a worse prognosis. The receptors and ectonucleotidases involved with BC become possible therapeutic targets. Several purinergic pathways have been found to be involved in BC cell survival and progression. In this review, in addition to analyzing the pathways involved, we reviewed the therapeutic interventions already studied for BC related to the purinergic system, as well as to other possible therapeutic targets.
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22
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Sharma S, Kalra H, Akundi RS. Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2. Front Pharmacol 2021; 11:617211. [PMID: 33584298 PMCID: PMC7873692 DOI: 10.3389/fphar.2020.617211] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
The tumor microenvironment plays a major role in the ability of the tumor cells to undergo metastasis. A major player of tumors gaining metastatic property is the inflammatory protein, cyclooxygenase 2 (COX-2). Several tumors show upregulation of this protein, which has been implicated in mediating metastasis in various cancer types such as of colon, breast and lung. In this report, we show that the concentration of extracellular ATP (eATP) is increased in response to cell death mediated by chemotherapeutic agents such as doxorubicin. By using three different cell-lines-HeLa (cervical), IMR-32 (neuronal) and MCF-7 (breast)-we show that this eATP goes on to act on purinergic (P2) receptors. Among the various P2 receptors expressed in these cells we identified P2X7, in IMR-32 and MCF-7 cells, and P2Y12, in HeLa cells, as important in modulating cell migration and invasion. Downstream of the P2 receptor activation, both p42/44 mitogen-activated protein kinase (MAPK) and the p38 MAPK are activated in these cells. These result in an increase in the expression of COX-2 mRNA and protein. We also observe an increase in the activity of matrix metalloproteinase 2 (MMP-2) enzyme in these cells. Blocking the P2 receptors not only blocks migration and invasion, but also COX-2 synthesis and MMP-2 activity. Our results show the link between purinergic receptors and COX-2 expression. Increased levels of ATP in the tumor microenvironment, therefore, leads to increased COX-2 expression, which, in turn, affords migratory and invasive properties to the tumor. This provides P2 receptor-based anti-inflammatory drugs (PBAIDs) a potential opportunity to be explored as cancer therapeutics.
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Affiliation(s)
- Shilpa Sharma
- Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Harshit Kalra
- Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Ravi Shankar Akundi
- Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
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23
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Zhu X, Li Q, Song W, Peng X, Zhao R. P2X7 receptor: a critical regulator and potential target for breast cancer. J Mol Med (Berl) 2021; 99:349-358. [PMID: 33486566 DOI: 10.1007/s00109-021-02041-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/24/2022]
Abstract
Breast cancer is currently the most common cancer and the leading cause of cancer death among women worldwide. Advanced breast cancer is prone to metastasis, and there is currently no drug to cure metastatic breast cancer. The purinergic ligand-gated ion channel 7 receptor is an ATP-gated nonselective cation channel receptor and is involved in signal transduction, growth regulation, cytokine secretion, and tumor cell development. Recent studies have shown that upregulation of the P2X7 receptor in breast cancer can mediate AKT signaling pathways, Ca2 þ-activated SK3 potassium channels, and EMT and regulate the secretion of small extracellular vesicles to promote breast cancer invasion and migration, which are affected by factors such as hypoxia and ATP. In addition, studies have shown that microRNAs can bind to the 3' untranslated region of the P2X7 receptor, which affects the occurrence and development of breast cancer by upregulating and downregulating P2X7 receptor expression. Studies have shown that new P2X7 receptor inhibitors, such as emodin and Uncaria tomentosa, can inhibit P2X7 receptor-mediated breast cancer invasion and are expected to be used clinically. This article reviews the research progress on the relationship between the P2X7 receptor and breast cancer to provide new ideas and a basis for clinical diagnosis and treatment.
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Affiliation(s)
- Xiaodi Zhu
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Qianqian Li
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Wei Song
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China
| | - Xiaoxiang Peng
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China.
| | - Ronglan Zhao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, China.
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Woods LT, Forti KM, Shanbhag VC, Camden JM, Weisman GA. P2Y receptors for extracellular nucleotides: Contributions to cancer progression and therapeutic implications. Biochem Pharmacol 2021; 187:114406. [PMID: 33412103 DOI: 10.1016/j.bcp.2021.114406] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 12/31/2020] [Indexed: 12/16/2022]
Abstract
Purinergic receptors for extracellular nucleotides and nucleosides contribute to a vast array of cellular and tissue functions, including cell proliferation, intracellular and transmembrane ion flux, immunomodulation and thrombosis. In mammals, the purinergic receptor system is composed of G protein-coupled P1 receptors A1, A2A, A2B and A3 for extracellular adenosine, P2X1-7 receptors that are ATP-gated ion channels and G protein-coupled P2Y1,2,4,6,11,12,13 and 14 receptors for extracellular ATP, ADP, UTP, UDP and/or UDP-glucose. Recent studies have implicated specific P2Y receptor subtypes in numerous oncogenic processes, including cancer tumorigenesis, metastasis and chemotherapeutic drug resistance, where G protein-mediated signaling cascades modulate intracellular ion concentrations and activate downstream protein kinases, Src family kinases as well as numerous mitogen-activated protein kinases. We are honored to contribute to this special issue dedicated to the founder of the field of purinergic signaling, Dr. Geoffrey Burnstock, by reviewing the diverse roles of P2Y receptors in the initiation, progression and metastasis of specific cancers with an emphasis on pharmacological and genetic strategies employed to delineate cell-specific and P2Y receptor subtype-specific responses that have been investigated using in vitro and in vivo cancer models. We further highlight bioinformatic and empirical evidence on P2Y receptor expression in human clinical specimens and cover clinical perspectives where P2Y receptor-targeting interventions may have therapeutic relevance to cancer treatment.
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Affiliation(s)
- Lucas T Woods
- Department of Biochemistry, University of Missouri, Columbia, MO, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Kevin Muñoz Forti
- Department of Biochemistry, University of Missouri, Columbia, MO, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Vinit C Shanbhag
- Department of Biochemistry, University of Missouri, Columbia, MO, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Jean M Camden
- Department of Biochemistry, University of Missouri, Columbia, MO, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Gary A Weisman
- Department of Biochemistry, University of Missouri, Columbia, MO, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
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25
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Yang T, Wang P, Yin X, Zhang J, Huo M, Gao J, Li G, Teng X, Yu H, Huang W, Wang Y. The histone deacetylase inhibitor PCI-24781 impairs calcium influx and inhibits proliferation and metastasis in breast cancer. Am J Cancer Res 2021; 11:2058-2076. [PMID: 33500709 PMCID: PMC7797697 DOI: 10.7150/thno.48314] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 11/29/2020] [Indexed: 12/14/2022] Open
Abstract
Histone deacetylases (HDACs) are involved in key cellular processes and have been implicated in cancer. As such, compounds that target HDACs or drugs that target epigenetic markers may be potential candidates for cancer therapy. This study was therefore aimed to identify a potential epidrug with low toxicity and high efficiency as anti-tumor agents. Methods: We first screened an epigenetic small molecule inhibitor library to screen for an epidrug for breast cancer. The candidate was identified as PCI-24781 and was characterized for half maximal inhibitory concentration (IC50), for specificity to breast cancer cells, and for effects on carcinogenesis and metastatic properties of breast cancer cell lines in vitro. A series of in silico and in vitro analyses were further performed of PCI-24781 to identify and understand its target. Results: Screening of an epigenetic inhibitor library in MDA-MB-231 cells, a malignant cancer cell line, showed that PCI-24781 is a potential anti-tumor drug specific to breast cancer. Ca2+ related pathways were identified as a potential target of PCI-24781. Further analyses showed that PCI-24781 inhibited Gαq-PLCβ3-mediated calcium signaling by activating the expression of regulator of G-protein signaling 2 (RGS2) to reduce cell proliferation, metastasis, and differentiation, resulting in cell death in breast cancer. In addition, RGS2 depletion reversed anti-tumor effect and inhibition of calcium influx induced by PCI-24781 treatment in breast cancer cells. Conclusions: We have demonstrated that PCI-24781 is an effective anti-tumor therapeutic agent that targets calcium signaling by activating RGS2. This study also provides a novel perspective into the use of HDAC inhibitors for cancer therapy.
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Pratt SJP, Hernández-Ochoa E, Martin SS. Calcium signaling: breast cancer's approach to manipulation of cellular circuitry. Biophys Rev 2020; 12:1343-1359. [PMID: 33569087 PMCID: PMC7755621 DOI: 10.1007/s12551-020-00771-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Calcium is a versatile element that participates in cell signaling for a wide range of cell processes such as death, cell cycle, division, migration, invasion, metabolism, differentiation, autophagy, transcription, and others. Specificity of calcium in each of these processes is achieved through modulation of intracellular calcium concentrations by changing the characteristics (amplitude/frequency modulation) or location (spatial modulation) of the signal. Breast cancer utilizes calcium signaling as an advantage for survival and progression. This review integrates evidence showing that increases in expression of calcium channels, GPCRs, pumps, effectors, and enzymes, as well as resulting intracellular calcium signals, lead to high calcium and/or an elevated calcium- mobilizing capacity necessary for malignant functions such as migratory, invasive, proliferative, tumorigenic, or metastatic capacities.
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Affiliation(s)
- Stephen J P Pratt
- Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore Street, Bressler Research Building, Rm 10-020 D, Baltimore, MD 21201 USA
| | - Erick Hernández-Ochoa
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD USA
| | - Stuart S Martin
- Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore Street, Bressler Research Building, Rm 10-020 D, Baltimore, MD 21201 USA
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Adiga D, Radhakrishnan R, Chakrabarty S, Kumar P, Kabekkodu SP. The Role of Calcium Signaling in Regulation of Epithelial-Mesenchymal Transition. Cells Tissues Organs 2020; 211:134-156. [PMID: 33316804 DOI: 10.1159/000512277] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 10/13/2020] [Indexed: 11/19/2022] Open
Abstract
Despite substantial advances in the field of cancer therapeutics, metastasis is a significant challenge for a favorable clinical outcome. Epithelial to mesenchymal transition (EMT) is a process of acquiring increased motility, invasiveness, and therapeutic resistance by cancer cells for their sustained growth and survival. A plethora of intrinsic mechanisms and extrinsic microenvironmental factors drive the process of cancer metastasis. Calcium (Ca2+) signaling plays a critical role in dictating the adaptive metastatic cell behavior comprising of cell migration, invasion, angiogenesis, and intravasation. By modulating EMT, Ca2+ signaling can regulate the complexity and dynamics of events leading to metastasis. This review summarizes the role of Ca2+ signal remodeling in the regulation of EMT and metastasis in cancer.
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Affiliation(s)
- Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India.,Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, India
| | - Prashant Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore, India.,Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India, .,Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, India,
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28
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Azimi I, Robitaille M, Armitage K, So CL, Milevskiy MJG, Northwood K, Lim HF, Thompson EW, Roberts-Thomson SJ, Monteith GR. Activation of the Ion Channel TRPV4 Induces Epithelial to Mesenchymal Transition in Breast Cancer Cells. Int J Mol Sci 2020; 21:ijms21249417. [PMID: 33322037 PMCID: PMC7764818 DOI: 10.3390/ijms21249417] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/03/2020] [Accepted: 12/08/2020] [Indexed: 12/16/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) in cancer is important in therapeutic resistance and invasiveness. Calcium signaling is key to the induction of EMT in breast cancer cells. Although inhibition of specific calcium-permeable ion channels regulates the induction of a sub-set of EMT markers in breast cancer cells, it is still unclear if activation of a specific calcium channel can be a driver for the induction of EMT events. In this study, we exploited the availability of a selective pharmacological activator of the calcium-permeable ion channel TRPV4 to assess the direct role of calcium influx in EMT marker induction. Gene association studies revealed a link between TRPV4 and gene-ontologies associated with EMT and poorer relapse-free survival in lymph node-positive basal breast cancers. TRPV4 was an important component of the calcium influx phase induced in MDA-MB-468 breast cancer cells by the EMT inducer epidermal growth factor (EGF). Pharmacological activation of TRPV4 then drove the induction of a variety of EMT markers in breast cancer cells. These studies demonstrate that calcium influx through specific pathways appears to be sufficient to trigger EMT events.
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Affiliation(s)
- Iman Azimi
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart, TAS 7005, Australia;
| | - Mélanie Robitaille
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; (M.R.); (K.A.); (C.L.S.); (H.F.L.); (S.J.R.-T.)
| | - Kaela Armitage
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; (M.R.); (K.A.); (C.L.S.); (H.F.L.); (S.J.R.-T.)
| | - Choon Leng So
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; (M.R.); (K.A.); (C.L.S.); (H.F.L.); (S.J.R.-T.)
| | - Michael J. G. Milevskiy
- ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
| | - Korinne Northwood
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD 4067, Australia;
- UQ Centre for Clinical Research, The University of Queensland, Herston, QLD 4029, Australia
| | - Huai Fang Lim
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; (M.R.); (K.A.); (C.L.S.); (H.F.L.); (S.J.R.-T.)
| | - Erik W. Thompson
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4102, Australia;
- Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
- Department of Surgery, St. Vincent’s Hospital, University of Melbourne, Melbourne, VIC 3065, Australia
| | - Sarah J. Roberts-Thomson
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; (M.R.); (K.A.); (C.L.S.); (H.F.L.); (S.J.R.-T.)
| | - Gregory R. Monteith
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; (M.R.); (K.A.); (C.L.S.); (H.F.L.); (S.J.R.-T.)
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
- Correspondence: ; Tel.: +61-7-334-61855
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Zhang WJ, Hu CG, Luo HL, Zhu ZM. Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling. Front Cell Dev Biol 2020; 8:586555. [PMID: 33330466 PMCID: PMC7732635 DOI: 10.3389/fcell.2020.586555] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/26/2020] [Indexed: 12/18/2022] Open
Abstract
The pathological mechanism of colon cancer is very complicated. Therefore, exploring the molecular basis of the pathogenesis of colon cancer and finding a new therapeutic target has become an urgent problem to be solved in the treatment of colon cancer. ATP plays an important role in regulating the progression of tumor cells. P2 × 7 belongs to ATP ion channel receptor, which is involved in the progression of tumors. In this study, we explored the effect and molecular mechanism of ATP-mediated P2 × 7 receptor on the migration and metastasis of colon cancer cells. The results showed that ATP and BzATP significantly increased the inward current and intracellular calcium concentration of LOVO and SW480 cells, while the use of antagonists (A438079 and AZD9056) could reverse the above phenomenon. We found that ATP promoted the migration and invasion of LOVO and SW480 cells and is dose-dependent on ATP concentration (100–300 μM). Similarly, BzATP (10, 50, and 100 μM) also significantly promoted the migration and invasion of colon cancer cells in a concentration-dependent manner. While P2 × 7 receptor antagonists [A438079 (10 μM), AZD9056 (10 μM)] or P2 × 7 siRNA could significantly inhibit ATP-induced colon cancer cell migration and invasion. Moreover, in vivo experiments showed that ATP-induced activation of P2 × 7 receptor promoted the growth of tumors. Furthermore, P2 × 7 receptor activation down-regulated E-cadherin protein expression and up-regulated MMP-2 mRNA and concentration levels. Knocking down the expression of P2 × 7 receptor could significantly inhibit the increase in the expression of N-cadherin, Vimentin, Zeb1, and Snail induced by ATP. In addition, ATP time-dependently induced the activation of STAT3 via the P2 × 7 receptor, and the STAT3 pathway was required for the ATP-mediated invasion and migration. Our conclusion is that ATP-induced P2 × 7 receptor activation promotes the migration and invasion of colon cancer cells, possibly via the activation of STAT3 pathway. Therefore, the P2 × 7 receptor may be a potential target for the treatment of colon cancer.
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Affiliation(s)
- Wen-Jun Zhang
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Ce-Gui Hu
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Hong-Liang Luo
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
| | - Zheng-Ming Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, China
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The calcium pump PMCA4 prevents epithelial-mesenchymal transition by inhibiting NFATc1-ZEB1 pathway in gastric cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118833. [PMID: 32860837 DOI: 10.1016/j.bbamcr.2020.118833] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 08/15/2020] [Accepted: 08/18/2020] [Indexed: 12/12/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is considered as the key mechanism involved in cancer metastasis. Several studies showed that various cell membrane calcium channels play different roles in cancer metastasis. In the present study, the potential role of ATPase plasma membrane Ca2+ transporting 4 (PMCA4) in regulating EMT in gastric cancer (GC) was investigated. GC patients who underwent radical surgery were enrolled in this study. In vitro human GC cell lines MKN45 and NCI-N87 were used, and MKN45 cells were injected in nude mice to evaluate tumor development. Our results showed that low PMCA4 expression was associated with advanced TNM stage and poor prognosis in GC patients. Knockdown of PMCA4 suppressed E-cadherin, grainyhead like 2 (GRHL2) and ovo-like 1 (OVOL1) expression, up-regulated vimentin expression, increased migration and invasion ability, and promoted the resistance to cytotoxic drug. Furthermore, GC cells displayed an elongated fibroblastoid morphology when PMCA4 was knockdown. PMCA4 overexpression resulted in an up-regulated E-cadherin expression and decreased migration and invasion ability. In vivo metastasis assay showed that PMCA4 overexpression resulted in a decreased incidence of lung metastasis. PMCA4 inhibition increased ZEB1 expression and nuclear accumulation of nuclear factor of activated T-cell isoform c1 (NFATc1). EMT induced by PMCA4 inhibition could be prevented by the knockdown of NFATc1 or ZEB1. In addition, cyclosporine A prevented EMT induced by PMCA4 inhibition by suppressing the NFATc1-ZEB1 pathway. Our data identified a novel mechanism in the regulation of EMT in GC, and provided a novel target in the treatment of EMT subtype in GC.
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31
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Arnaud-Sampaio VF, Rabelo ILA, Bento CA, Glaser T, Bezerra J, Coutinho-Silva R, Ulrich H, Lameu C. Using Cytometry for Investigation of Purinergic Signaling in Tumor-Associated Macrophages. Cytometry A 2020; 97:1109-1126. [PMID: 32633884 DOI: 10.1002/cyto.a.24035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/25/2020] [Accepted: 04/01/2020] [Indexed: 02/06/2023]
Abstract
Tumor-associated macrophages are widely recognized for their importance in guiding pro-tumoral or antitumoral responses. Mediating inflammation or immunosuppression, these cells support many key events in cancer progression: cell growth, chemotaxis, invasiveness, angiogenesis and cell death. The communication between cells in the tumor microenvironment strongly relies on the secretion and recognition of several molecules, including damage-associated molecular patterns (DAMPs), such as adenosine triphosphate (ATP). Extracellular ATP (eATP) and its degradation products act as signaling molecules and have extensively described roles in immune response and inflammation, as well as in cancer biology. These multiple functions highlight the purinergic system as a promising target to investigate the interplay between macrophages and cancer cells. Here, we reviewed purinergic signaling pathways connecting cancer cells and macrophages, a yet poorly investigated field. Finally, we present a new tool for the characterization of macrophage phenotype within the tumor. Image cytometry emerges as a cutting-edge tool, capable of providing a broad set of information on cell morphology, expression of specific markers, and its cellular or subcellular localization, preserving cell-cell interactions within the tumor section and providing high statistical strength in small-sized experiments. Thus, image cytometry allows deeper investigation of tumor heterogeneity and interactions between these cells. © 2020 International Society for Advancement of Cytometry.
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Affiliation(s)
| | - Izadora L A Rabelo
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Carolina A Bento
- 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
| | - Jean Bezerra
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Robson Coutinho-Silva
- Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Henning Ulrich
- 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
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32
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Zhang KD, Hu B, Cen G, Yang YH, Chen WW, Guo ZY, Wang XF, Zhao Q, Qiu ZJ. MiR-301a transcriptionally activated by HIF-2α promotes hypoxia-induced epithelial-mesenchymal transition by targeting TP63 in pancreatic cancer. World J Gastroenterol 2020; 26:2349-2373. [PMID: 32476798 PMCID: PMC7243651 DOI: 10.3748/wjg.v26.i19.2349] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/20/2010] [Accepted: 04/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is one of the deadliest cancers worldwide. PC metastasis involves a complex set of events, including epithelial-mesenchymal transition (EMT), that increase tumor cell invasiveness. Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis; however, the mechanisms remain elusive. AIM To investigate the role of miR-301a in hypoxia-induced EMT in PC cells. METHODS Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions. Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression. Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout. Luciferase assay was used to detect the miR-301a promoter and the 3' untranslated region activity of TP63. Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo. In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples (adjacent paratumor and paired tumor tissues). . RESULTS Hypoxic environment could directly promote the EMT of PC cells. The expression level of miR-301a was increased in a HIF2α dependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells. Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells, while knocking out miR-301a result in the suppression of hypoxia-induced EMT. TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells. Furthermore, miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo. Additionally, miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis. CONCLUSION The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.
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MESH Headings
- 3' Untranslated Regions/genetics
- Animals
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Cell Hypoxia/genetics
- Cell Line, Tumor
- Epithelial-Mesenchymal Transition/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Gene Knockout Techniques
- Humans
- Kaplan-Meier Estimate
- Male
- Mice
- MicroRNAs/analysis
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Middle Aged
- Pancreas/pathology
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Prognosis
- Promoter Regions, Genetic/genetics
- Signal Transduction/genetics
- Transcription Factors/genetics
- Tumor Suppressor Proteins/genetics
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Kun-Dong Zhang
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Bin Hu
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Gang Cen
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Yu-Han Yang
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Wei-Wei Chen
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Zeng-Ya Guo
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Xiao-Feng Wang
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Qian Zhao
- Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology and Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zheng-Jun Qiu
- Department of General Surgery, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
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Analysis of purine receptor expression and functionality in alveolar epithelial cells. Purinergic Signal 2020; 16:213-229. [PMID: 32236789 DOI: 10.1007/s11302-020-09696-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/06/2020] [Indexed: 02/07/2023] Open
Abstract
Despite its fundamental role in providing an extensive surface for gas exchange, the alveolar epithelium (AE) serves as an immunological barrier through, e.g., the release of proinflammatory cytokines and secretion of surfactant to prevent alveolar collapse. Thus, AE is important for sustaining lung homeostasis. Extracellular ATP secreted by alveolar epithelial cells (AECs) is involved in physiological and pathological conditions and acts mainly through the activation of purine receptors (P2Rs). When studying P2R-mediated processes, primary isolated type II AECs (piAECs) still represent the gold standard in in vitro research, although their preparation is time-consuming and requires the sacrifice of many animals. Hence, cultivated immortalized and tumor-derived AEC lines may constitute a valuable alternative. In this work, we examined P2R expression and functionality in piAECs, in immortalized and tumor-derived AEC lines with the purpose of gaining a better understanding of purinergic signaling in different cell systems and assisting researchers in the choice of a suitable cell line with a certain P2R in demand. We combined mRNA and protein analysis to evaluate the expression of P2R. For pharmacological testing, we conducted calcium ([Ca2+]) measurements and siRNA receptor knockdown. Interestingly, the mRNA and protein levels of P2Y2, P2Y6, and P2X4 were detected on all cell lines. Concerning functionality, P2XR could be narrowed to L2 and piAECs while P2YR were active in all cell lines.
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Girault A, Ahidouch A, Ouadid-Ahidouch H. Roles for Ca 2+ and K + channels in cancer cells exposed to the hypoxic tumour microenvironment. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118644. [PMID: 31931022 DOI: 10.1016/j.bbamcr.2020.118644] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 12/26/2019] [Accepted: 12/31/2019] [Indexed: 02/07/2023]
Abstract
For twenty years, ion channels have been studied in cancer progression. Several information have been collected about their involvement in cancer cellular processes like cell proliferation, motility and their participation in tumour progression using in-vivo models. Tumour microenvironment is currently the focus of many researches and the highlighting of the relationship between cancer cells and surrounding elements, is expanding. One of the major physic-chemical parameter involved in tumour progression is the hypoxia conditions observed in solid cancer. Due to their position on the cell membrane, ion channels are good candidates to transduce or to be modulated by environmental modifications. Until now, few reports have been interested in the modification of ion channel activities or expression in this context, compared to other pathological situations such as ischemia reperfusion. The aim of our review is to summarize the current knowledge about the calcium and potassium channels properties in the context of hypoxia in tumours. This review could pave the way to orientate new studies around this exciting field to obtain new potential therapeutic approaches.
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Affiliation(s)
- Alban Girault
- Université de Picardie Jules Verne, UFR des Sciences, Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), Amiens, France
| | - Ahmed Ahidouch
- Université de Picardie Jules Verne, UFR des Sciences, Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), Amiens, France; Université Ibn Zohr, Faculté des sciences, Département de Biologie, Agadir, Morocco
| | - Halima Ouadid-Ahidouch
- Université de Picardie Jules Verne, UFR des Sciences, Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), Amiens, France.
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Asif A, Khalid M, Manzoor S, Ahmad H, Rehman AU. Role of purinergic receptors in hepatobiliary carcinoma in Pakistani population: an approach towards proinflammatory role of P2X4 and P2X7 receptors. Purinergic Signal 2019; 15:367-374. [PMID: 31401785 PMCID: PMC6737133 DOI: 10.1007/s11302-019-09675-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
The primary malignancy of liver, known as hepatocellular carcinoma (HCC), comprises 9% of all hepatobiliary carcinomas. A steady rise has also been observed in adenocarcinoma (ADC) of the liver and ampullary carcinoma (AMC), ascending to 0.5% of gastrointestinal malignancies. Hepatobiliary carcinomas consist of 13% of all cancer occurrences worldwide. Purinergic receptor-based signaling holds the therapeutic potential based on its role in cell proliferation of several carcinomas. An altered ATP concentration in nanomoles may lead towards crucial changes in cancer growth patterns in liver tissue. A total of 40 tissue samples were collected (20 samples of HCC, 10 samples of ADC, and 10 samples of AMC) from patients that underwent surgery. P2X4 and P2X7 receptors exhibited significantly increased expression in HCC, ADC, and AMC samples as compared with the control tissue samples. While ADC and AMC samples showed higher expression of P2X4 and P2X7 than the control, statistically, HCC samples exhibited the most significant expression of both P2X4 and P2X7 receptors than control tissues. It may be inferred that higher expression of P2X4 and P2X7 receptors is significantly associated with the upregulated cellular stress leading to inflammation and it is plausible that both these receptors may be used in diagnostic, prognostic, and therapeutic tools for carcinoma studies in the future.
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Affiliation(s)
- Arun Asif
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, H-12, Islamabad, 44000, Pakistan
| | - Madiha Khalid
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, H-12, Islamabad, 44000, Pakistan
| | - Sobia Manzoor
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, H-12, Islamabad, 44000, Pakistan.
| | - Hassam Ahmad
- Hepato-pancreatobiliary Liver Transplant Unit, Shaikh Zayd Hospital, Lahore, Punjab, 54000, Pakistan
| | - Aman Ur Rehman
- Department of Histopathology, Shaikh Zayd Hospital, Lahore, Punjab, 54000, Pakistan
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Roberts-Thomson SJ, Chalmers SB, Monteith GR. The Calcium-Signaling Toolkit in Cancer: Remodeling and Targeting. Cold Spring Harb Perspect Biol 2019; 11:cshperspect.a035204. [PMID: 31088826 DOI: 10.1101/cshperspect.a035204] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Processes that are important in cancer progression, such as sustained cell growth, invasion to other organs, and resistance to cell death inducers, have a clear overlap with pathways regulated by Ca2+ signaling. It is therefore not surprising that proteins important in Ca2+ signaling, sometimes referred to as the "Ca2+ signaling toolkit," can contribute to cancer cell proliferation and invasiveness, and the ability of agents to induce cancer cell death. Ca2+ signaling is also critical in other aspects of cancer progression, including events in the tumor microenvironment and processes involved in the acquisition of resistance to anticancer therapies. This review will consider the role of Ca2+ signaling in tumor progression and highlight areas in which a better understanding of the interplay between the Ca2+-signaling toolkit and tumorigenesis is still required.
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Affiliation(s)
| | - Silke B Chalmers
- The School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Gregory R Monteith
- The School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072, Australia.,Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland 4072, Australia
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ER Ca 2+ release and store-operated Ca 2+ entry - partners in crime or independent actors in oncogenic transformation? Cell Calcium 2019; 82:102061. [PMID: 31394337 DOI: 10.1016/j.ceca.2019.102061] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/21/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023]
Abstract
Ca2+ is a pleiotropic messenger that controls life and death decisions from fertilisation until death. Cellular Ca2+ handling mechanisms show plasticity and are remodelled throughout life to meet the changing needs of the cell. In turn, as the demands on a cell alter, for example through a change in its niche environment or its functional requirements, Ca2+ handling systems may be targeted to sustain the remodelled cellular state. Nowhere is this more apparent than in cancer. Oncogenic transformation is a multi-stage process during which normal cells become progressively differentiated towards a cancerous state that is principally associated with enhanced proliferation and avoidance of death. Ca2+ signalling is intimately involved in almost all aspects of the life of a transformed cell and alterations in Ca2+ handling have been observed in cancer. Moreover, this remodelling of Ca2+ signalling pathways is also required in some cases to sustain the transformed phenotype. As such, Ca2+ handling is hijacked by oncogenic processes to deliver and maintain the transformed phenotype. Central to generation of intracellular Ca2+ signals is the release of Ca2+ from the endoplasmic reticulum intracellular (ER) Ca2+ store via inositol 1,4,5-trisphosphate receptors (InsP3Rs). Upon depletion of ER Ca2+, store-operated Ca2+ entry (SOCE) across the plasma membrane occurs via STIM-gated Orai channels. SOCE serves to both replenish stores but also sustain Ca2+ signalling events. Here, we will discuss the role and regulation of these two signalling pathways and their interplay in oncogenic transformation.
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Scarpellino G, Genova T, Munaron L. Purinergic P2X7 Receptor: A Cation Channel Sensitive to Tumor Microenvironment. Recent Pat Anticancer Drug Discov 2019; 14:32-38. [DOI: 10.2174/1574892814666190116122256] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 01/06/2019] [Accepted: 01/07/2019] [Indexed: 02/06/2023]
Abstract
Background: Purinergic signalling is involved in several physiological and pathophysiological processes. P2X7 Receptor (P2X7R) is a calcium-permeable ion channel that is gaining interest as a potential therapeutic target for the treatment of different diseases including inflammation, pain, psychiatric disorders and cancer. P2X7R is ubiquitously expressed and sensitive to high ATP levels, usually found in tumor microenvironment. P2X7R regulates several cell functions, from migration to cell death, but its selective contribution to tumor progression remains controversial.Objective:Current review was conducted to check involvement of P2X7R use in cancer treatment.Methods:We review the most recent patents focused on the use of P2X7R in the treatment of cancer.Results:P2X7R is an intriguing purinergic receptor that plays different roles in tumor progression.Conclusion:Powerful strategies able to selectively interfere with its expression and function should reveal helpful in the development of new anti-cancer therapies.
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Affiliation(s)
- Giorgia Scarpellino
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Tullio Genova
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Luca Munaron
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
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Liu L, Wu N, Wang Y, Zhang X, Xia B, Tang J, Cai J, Zhao Z, Liao Q, Wang J. TRPM7 promotes the epithelial-mesenchymal transition in ovarian cancer through the calcium-related PI3K / AKT oncogenic signaling. J Exp Clin Cancer Res 2019; 38:106. [PMID: 30819230 PMCID: PMC6396458 DOI: 10.1186/s13046-019-1061-y] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/27/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear. METHODS The expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected. TRPM7was knockdown by shRNA in Ovarian cancer cell lines to examine calcium [Ca2+]i, EMT markers and PI3K/AKT markers. Various cellular assays, such as invasion and migration, were performed in vitro, and further confirmed in vivo. RESULTS TRPM7 expression is negatively correlated with E-cadherin, but positively with N-cadherin, Vimentin and Twist expression in ovarian cancer samples. TRPM7 depletion inhibited the migration and invasion in SKOV3 and OVCAR3 cells. In addition, TRPM7 silencing decreased the lung metastasis of SKOV3 tumors and prolonged the survival of tumor-bearing mice. Similar to that of TRPM7 silencing, treatment with MK886, a potent 5-lipoxygenase inhibitor to reduce TRPM7 expression, and/or BAPTA-AM, an intracellular calcium chelator, significantly mitigated the Epidermal growth factor (EGF) or Insulin-like growth factors (IGF)-stimulated migration, invasion, and the EMT in ovarian cancer cells by decreasing the levels of intracellular calcium [Ca2+]i. Furthermore, treatment with LY2904002, a PI3K inhibitor, also inhibited the migration, invasion, and treatment with both LY2904002 and BAPTA-AM further enhanced their inhibition in ovarian cancer cells. Moreover, treatment with BAPTA-AM mitigated the IGF-stimulated migration, invasion, particularly in TRPM7-silenced ovarian cancer cells. Finally, TRPM7 silencing attenuated the PI3K/AKT activation, which was enhanced by BAPTA-AM, MK886 or LY2904002 treatment in ovarian cancer cells. CONCLUSIONS TRPM7 silencing inhibited the EMT and metastasis of ovarian cancer by attenuating the calcium-related PI3k/AKT activation. Our findings suggest that TRPM7 may be a therapeutic target for intervention of ovarian cancer.
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Affiliation(s)
- Lu Liu
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
- University of South China, Hengyang, 421001 People’s Republic of China
| | - Nayiyuan Wu
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Ying Wang
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Xiaoyun Zhang
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Bing Xia
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Jie Tang
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Jingting Cai
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Zitong Zhao
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Qianjin Liao
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
| | - Jing Wang
- Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013 Hunan People’s Republic of China
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Azimi I, Milevskiy MJG, Chalmers SB, Yapa KTDS, Robitaille M, Henry C, Baillie GJ, Thompson EW, Roberts-Thomson SJ, Monteith GR. ORAI1 and ORAI3 in Breast Cancer Molecular Subtypes and the Identification of ORAI3 as a Hypoxia Sensitive Gene and a Regulator of Hypoxia Responses. Cancers (Basel) 2019; 11:E208. [PMID: 30754719 PMCID: PMC6406924 DOI: 10.3390/cancers11020208] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/01/2019] [Accepted: 02/04/2019] [Indexed: 01/12/2023] Open
Abstract
The remodeling of specific calcium-permeable ion channels is a feature of some breast cancer subtypes. ORAI1 is a protein that forms a calcium-permeable ion channel responsible for store-operated calcium entry (SOCE) in a variety of cell types. ORAI3, a related isoform, is not a regulator of SOCE in most cell types. However, ORAI3 does control SOCE in many estrogen receptor-positive breast cancer cell lines, where it also controls proliferation. ORAI1 is a well-characterized regulator of the proliferation and migration of many basal breast cancer cells; however, the role of ORAI3 in these types of breast cancer cells remains unclear. Here, we sought to define ORAI1 and ORAI3 expression in breast cancer cell lines of different molecular subtypes and assess the potential role and regulation of ORAI3 in basal breast cancer cells. Our study demonstrates that elevated ORAI1 is a feature of basal-like breast cancers, while elevated ORAI3 is a feature of luminal breast cancers. Intriguingly, we found that ORAI3 is over-expressed in the mesenchymal subtype of triple-negative breast cancer. Given this, we assessed ORAI3 levels in the presence of two inducers of the mesenchymal phenotype, hypoxia and epidermal growth factor (EGF). Hypoxia induced ORAI3 levels in basal breast cancer cell lines through a pathway involving hypoxia-inducible factor-1 alpha (HIF1α. The silencing of ORAI3 attenuated hypoxia-associated phosphorylation of the EGF receptor (EGFR) and the expression of genes associated with cell migration and inflammatory/immune responses in the MDA-MB-468 model of basal breast cancer. Although elevated ORAI3 levels were not associated with survival; basal, estrogen receptor-negative and triple-negative breast cancers with high ORAI3 and low ORAI1 levels were associated with poorer clinical outcomes. This study defines ORAI3 as a potential fine-tuner for processes relevant to the progression of basal breast cancers.
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Affiliation(s)
- Iman Azimi
- School of Pharmacy, The University of Queensland, Brisbane 4102, Queensland, Australia.
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane 4102, Queensland, Australia.
- Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart 7001, Tasmania, Australia.
| | - Michael J G Milevskiy
- ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.
| | - Silke B Chalmers
- School of Pharmacy, The University of Queensland, Brisbane 4102, Queensland, Australia.
| | - Kunsala T D S Yapa
- School of Pharmacy, The University of Queensland, Brisbane 4102, Queensland, Australia.
| | - Mélanie Robitaille
- School of Pharmacy, The University of Queensland, Brisbane 4102, Queensland, Australia.
| | - Christopher Henry
- School of Pharmacy, The University of Queensland, Brisbane 4102, Queensland, Australia.
| | - Gregory J Baillie
- Division of Genomics, Development and Disease, Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Queensland, Australia.
| | - Erik W Thompson
- Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane 4102, Queensland, Australia.
- University of Melbourne, Department of Surgery, St. Vincent's Hospital, Melbourne 3065, Victoria, Australia.
| | | | - Gregory R Monteith
- School of Pharmacy, The University of Queensland, Brisbane 4102, Queensland, Australia.
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane 4102, Queensland, Australia.
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Maklad A, Sharma A, Azimi I. Calcium Signaling in Brain Cancers: Roles and Therapeutic Targeting. Cancers (Basel) 2019; 11:cancers11020145. [PMID: 30691160 PMCID: PMC6406375 DOI: 10.3390/cancers11020145] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 01/22/2019] [Accepted: 01/23/2019] [Indexed: 02/06/2023] Open
Abstract
Calcium signaling, in addition to its numerous physiological roles, is also implicated in several pathological conditions including cancer. An increasing body of evidence suggest critical roles of calcium signaling in the promotion of different aspects of cancer, including cell proliferation, therapy resistance and metastatic-related processes. In many cases, this is associated with altered expression and/or activity of some calcium channels and pumps. Brain cancers have also been the subject of many of these studies. In addition to diverse roles of calcium signals in normal brain function, a number of proteins involved in calcium transport are implicated to have specific roles in some brain cancers including gliomas, medulloblastoma, neuroblastoma and meningioma. This review discusses research that has been conducted so far to understand diverse roles of Ca2+-transporting proteins in the progression of brain cancers, as well as any attempts to target these proteins towards a therapeutic approach for the control of brain cancers. Finally, some knowledge gaps in the field that may need to be further considered are also discussed.
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Affiliation(s)
- Ahmed Maklad
- Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7001, Australia.
| | - Anjana Sharma
- Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7001, Australia.
| | - Iman Azimi
- Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7001, Australia.
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Sharma S, Goswami R, Rahaman SO. The TRPV4-TAZ mechanotransduction signaling axis in matrix stiffness- and TGFβ1-induced epithelial-mesenchymal transition. Cell Mol Bioeng 2018; 12:139-152. [PMID: 31681446 DOI: 10.1007/s12195-018-00565-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Introduction The implantation of biomaterials into soft tissue leads to the development of foreign body response, a non-specific inflammatory condition that is characterized by the presence of fibrotic tissue. Epithelial-mesenchymal transition (EMT) is a key event in development, fibrosis, and oncogenesis. Emerging data support a role for both a mechanical signal and a biochemical signal in EMT. We hypothesized that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive channel, is a mediator of EMT. Methods Normal human primary epidermal keratinocytes (NHEKs) were seeded on collagen-coated plastic plates or varied stiffness polyacrylamide gels in the presence or absence of TGFβ1, Immunofluorescence, immunoblot, and polymerase chain reaction analysis were performed to determine expression level of EMT markers and signaling proteins. Knock-down of TRPV4 function was achieved by siRNA transfection or by GSK2193874 treatment. Results We found that knock-down of TRPV4 blocked both matrix stiffness- and TGFβ1-induced EMT in NHEKs. In a murine skin fibrosis model, TRPV4 deletion resulted in decreased expression of the mesenchymal marker, α-SMA, and increased expression of epithelial marker, E-cadherin. Mechanistically, our data showed that: i) TRPV4 was essential for the nuclear translocation of TAZ in response to matrix stiffness and TGFβ1; ii) Antagonism of TRPV4 inhibited both matrix stiffness-induced and TGFβ1-induced expression of TAZ proteins; and iii) TRPV4 antagonism suppressed both matrix stiffness-induced and TGFβ1-induced activation of Smad2/3, but not of AKT. Conclusions These data identify a novel role for TRPV4-TAZ mechanotransduction signaling axis in regulating EMT in NHEKs in response to both matrix stiffness and TGFβ1.
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Affiliation(s)
- Shweta Sharma
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742 USA
| | - Rishov Goswami
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742 USA
| | - Shaik O Rahaman
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742 USA
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Azimi I, Bong AH, Poo GXH, Armitage K, Lok D, Roberts-Thomson SJ, Monteith GR. Pharmacological inhibition of store-operated calcium entry in MDA-MB-468 basal A breast cancer cells: consequences on calcium signalling, cell migration and proliferation. Cell Mol Life Sci 2018; 75:4525-4537. [PMID: 30105615 PMCID: PMC11105359 DOI: 10.1007/s00018-018-2904-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 08/08/2018] [Accepted: 08/09/2018] [Indexed: 12/14/2022]
Abstract
Store-operated Ca2+ entry is a pathway that is remodelled in a variety of cancers, and altered expression of the components of store-operated Ca2+ entry is a feature of breast cancer cells of the basal molecular subtype. Studies of store-operated Ca2+ entry in breast cancer cells have used non-specific pharmacological inhibitors, complete depletion of intracellular Ca2+ stores and have mostly focused on MDA-MB-231 cells (a basal B breast cancer cell line). These studies compared the effects of the selective store-operated Ca2+ entry inhibitors Synta66 and YM58483 (also known as BTP2) on global cytosolic free Ca2+ ([Ca2+]CYT) changes induced by physiological stimuli in a different breast cancer basal cell line model, MDA-MB-468. The effects of these agents on proliferation as well as serum and epidermal growth factor (EGF) induced migration were also assessed. Activation with the purinergic receptor activator adenosine triphosphate, produced a sustained increase in [Ca2+]CYT that was entirely dependent on store-operated Ca2+ entry. The protease activated receptor 2 activator, trypsin, and EGF also produced Ca2+ influx that was sensitive to both Synta66 and YM58483. Serum-activated migration of MDA-MB-468 breast cancer cells was sensitive to both store-operated Ca2+ inhibitors. However, proliferation and EGF-activated migration was differentially affected by Synta66 and YM58483. These studies highlight the need to define the exact mechanisms of action of different store-operated calcium entry inhibitors and the impact of such differences in the control of tumour progression pathways.
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Affiliation(s)
- Iman Azimi
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Alice H Bong
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| | - Greta X H Poo
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| | - Kaela Armitage
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| | - Dawn Lok
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| | | | - Gregory R Monteith
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.
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P2Y 11 Receptors: Properties, Distribution and Functions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1051:107-122. [PMID: 29134605 DOI: 10.1007/5584_2017_89] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The P2Y11 receptor is a G protein-coupled receptor that is stimulated by endogenous purine nucleotides, particularly ATP. Amongst P2Y receptors it has several unique properties; (1) it is the only human P2Y receptor gene that contains an intron in the coding sequence; (2) the gene does not appear to be present in the rodent genome; (3) it couples to stimulation of both phospholipase C and adenylyl cyclase. Its absence in mice and rats, along with a limited range of selective pharmacological tools, has hampered the development of our knowledge and understanding of its properties and functions. Nonetheless, through a combination of careful use of the available tools, suppression of receptor expression using siRNA and genetic screening for SNPs, possible functions of native P2Y11 receptors have been identified in a variety of human cells and tissues. Many are in blood cells involved in inflammatory responses, consistent with extracellular ATP being a damage-associated signalling molecule in the immune system. Thus proposed potential therapeutic applications relate, in the main, to modulation of acute and chronic inflammatory responses.
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45
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Pratt SJP, Hernández-Ochoa EO, Lee RM, Ory EC, Lyons JS, Joca HC, Johnson A, Thompson K, Bailey P, Lee CJ, Mathias T, Vitolo MI, Trudeau M, Stains JP, Ward CW, Schneider MF, Martin SS. Real-time scratch assay reveals mechanisms of early calcium signaling in breast cancer cells in response to wounding. Oncotarget 2018; 9:25008-25024. [PMID: 29861849 PMCID: PMC5982755 DOI: 10.18632/oncotarget.25186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 04/03/2018] [Indexed: 01/11/2023] Open
Abstract
Aggressive cellular phenotypes such as uncontrolled proliferation and increased migration capacity engender cellular transformation, malignancy and metastasis. While genetic mutations are undisputed drivers of cancer initiation and progression, it is increasingly accepted that external factors are also playing a major role. Two recently studied modulators of breast cancer are changes in the cellular mechanical microenvironment and alterations in calcium homeostasis. While many studies investigate these factors separately in breast cancer cells, very few do so in combination. This current work sets a foundation to explore mechano-calcium relationships driving malignant progression in breast cancer. Utilizing real-time imaging of an in vitro scratch assay, we were able to resolve mechanically-sensitive calcium signaling in human breast cancer cells. We observed rapid initiation of intracellular calcium elevations within seconds in cells at the immediate wound edge, followed by a time-dependent increase in calcium in cells at distances up to 500μm from the scratch wound. Calcium signaling to neighboring cells away from the wound edge returned to baseline within seconds. Calcium elevations at the wound edge however, persisted for up to 50 minutes. Rigorous quantification showed that extracellular calcium was necessary for persistent calcium elevation at the wound edge, but intercellular signal propagation was dependent on internal calcium stores. In addition, intercellular signaling required extracellular ATP and activation of P2Y2 receptors. Through comparison of scratch-induced signaling from multiple cell lines, we report drastic reductions in response from aggressively tumorigenic and metastatic cells. The real-time scratch assay established here provides quantitative data on the molecular mechanisms that support rapid scratch-induced calcium signaling in breast cancer cells. These mechanisms now provide a clear framework for investigating which short-term calcium signals promote long-term changes in cancer cell biology.
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Affiliation(s)
- Stephen J P Pratt
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Erick O Hernández-Ochoa
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Rachel M Lee
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eleanor C Ory
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - James S Lyons
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Humberto C Joca
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Ashley Johnson
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Keyata Thompson
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Patrick Bailey
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Cornell J Lee
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Trevor Mathias
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Michele I Vitolo
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Matt Trudeau
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Joseph P Stains
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Christopher W Ward
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.,School of Nursing, University of Maryland, Baltimore, MD, USA
| | - Martin F Schneider
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Stuart S Martin
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
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Stevenson RJ, Azimi I, Flanagan JU, Inserra M, Vetter I, Monteith GR, Denny WA. An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca 2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay. Bioorg Med Chem 2018; 26:3406-3413. [PMID: 29776832 DOI: 10.1016/j.bmc.2018.05.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/01/2018] [Accepted: 05/08/2018] [Indexed: 12/30/2022]
Abstract
The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.
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Affiliation(s)
- Ralph J Stevenson
- Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
| | - Iman Azimi
- The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia; Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia; Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia
| | - Jack U Flanagan
- Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Marco Inserra
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Irina Vetter
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Gregory R Monteith
- The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia; Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - William A Denny
- Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
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47
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The therapeutic potential of purinergic signalling. Biochem Pharmacol 2018; 151:157-165. [DOI: 10.1016/j.bcp.2017.07.016] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 07/18/2017] [Indexed: 01/05/2023]
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Abstract
P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y2 (UTP, also ATP and dinucleotides), P2Y4 (UTP), P2Y6 (UDP), and P2Y14 (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y2R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y2R antagonist is AR-C118925 (10-01). For studies of the P2Y4R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) is a selective antagonist. Several potent P2Y6R agonists have been developed including 5-methoxyuridine 5'-O-((Rp)α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y6R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y14R agonist is available, while PPTN (10-14) represents a potent and selective P2Y14R antagonist. The radioligand [3H]UDP can be used to label P2Y14Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases.
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Assessment of the TRPM8 inhibitor AMTB in breast cancer cells and its identification as an inhibitor of voltage gated sodium channels. Life Sci 2018; 198:128-135. [DOI: 10.1016/j.lfs.2018.02.030] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 02/11/2018] [Accepted: 02/23/2018] [Indexed: 12/11/2022]
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Li S, Zhang T, Xu W, Ding J, Yin F, Xu J, Sun W, Wang H, Sun M, Cai Z, Hua Y. Sarcoma-Targeting Peptide-Decorated Polypeptide Nanogel Intracellularly Delivers Shikonin for Upregulated Osteosarcoma Necroptosis and Diminished Pulmonary Metastasis. Am J Cancer Res 2018; 8:1361-1375. [PMID: 29507626 PMCID: PMC5835942 DOI: 10.7150/thno.18299] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 12/18/2017] [Indexed: 12/18/2022] Open
Abstract
Purpose: Osteosarcoma is the most common primary bone cancer and is notorious for pulmonary metastasis, representing a major threat to pediatric patients. An effective drug targeting osteosarcoma and its lung metastasis is urgently needed. Design: In this study, a sarcoma-targeting peptide-decorated disulfide-crosslinked polypeptide nanogel (STP-NG) was exploited for enhanced intracellular delivery of shikonin (SHK), an extract of a medicinal herb, to inhibit osteosarcoma progression with minimal systemic toxicity. Results: The targeted, loaded nanogel, STP-NG/SHK, killed osteosarcoma cells by inducing RIP1- and RIP3-dependent necroptosis in vitro. Necroptosis is a novel cell death form that could be well adapted as an efficient antitumor strategy, the main obstacle of which is its high toxicity. After intravenous injection, STP-NG/SHK efficiently suppressed tumor growth and reduced pulmonary metastasis, offering greater tumor necrosis and higher RIP1 and RIP3 upregulation compared to free SHK or untargeted NG/SHK in vivo. Additionally, the treatment with NG/SHK or STP-NG/SHK showed minimal toxicity to normal organs, suggesting low systemic toxicity compared to free SHK. Conclusion: The STP-guided intracellular drug delivery system using the necroptosis mechanism showed profound anti-osteosarcoma activity, especially eliminated lung metastasis in vivo. This drug formulation may have great potential for treatment of osteosarcoma.
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