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Pathak T, Benson JC, Tang PW, Trebak M, Hempel N. Crosstalk between calcium and reactive oxygen species signaling in cancer revisited. Cell Calcium 2025; 127:103014. [PMID: 40139005 DOI: 10.1016/j.ceca.2025.103014] [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: 01/03/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
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Affiliation(s)
- Trayambak Pathak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - J Cory Benson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Priscilla W Tang
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mohamed Trebak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Nadine Hempel
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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Zhang Y, Yi Y, Shu Y, Ru X, He S. TRP channels and breast cancer: the role of TRPs in the pathophysiological development. Front Mol Biosci 2025; 12:1528663. [PMID: 40078961 PMCID: PMC11896876 DOI: 10.3389/fmolb.2025.1528663] [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: 11/15/2024] [Accepted: 01/27/2025] [Indexed: 03/14/2025] Open
Abstract
TRP channels play important roles in regulating various physiological and pathological processes, including the progression of cancer. Several TRP channels mediate tumour development. This review focuses on the role of TRP channels in the development of breast cancer, including their involvement in proliferation, apoptosis, autophagy, metastasis, and angiogenesis. TRP channels are associated with breast carcinogenesis and their role as potential therapeutic targets and prognostic biomarkers is under investigation. This review summarizes the reported effects of inhibiting or agonizing various TRP channel in breast cancer cells. Although there are relatively mature protocols for the treatment of breast cancer, its treatment is not currently a breakthrough, and therapies targeting TRP channels may be a developable strategy for it.
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Affiliation(s)
- Yu Zhang
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, China
| | - Yanfeng Yi
- Department of Life Sciences and Health, School of Science and Engineering, Huzhou College, Huzhou, China
| | - Yinghao Shu
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, China
| | - Xiaochen Ru
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, China
| | - Shuaibing He
- Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, China
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Díaz-Betancourt A, Galicia-Castillo ME, Morales-Tlalpan V, Chávez-Servín JL, Blanco-Labra A, García-Gasca T, Saldaña C. Tepary Bean ( Phaseolus acutifolius) Lectins as Modulators of Intracellular Calcium Mobilization in Breast Cancer and Normal Breast Cells. Int J Mol Sci 2025; 26:1064. [PMID: 39940827 PMCID: PMC11817043 DOI: 10.3390/ijms26031064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/24/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
Lectins are proteins that specifically recognize carbohydrates on cell membranes, triggering several cellular events such as apoptosis of cancer-transformed cells; however, the mechanisms of action remain incompletely understood. Our research group has reported that a concentrated fraction of Tepary bean lectins (Phaseolus acutifolius; TBLF) exhibits the concentration-dependent induction of apoptosis in colon cancer cells by caspase activation. It is well established that an increase in cytoplasmic calcium ([Ca2+]i) initiates intracellular signals involved in processes such as exocytosis, gene transcription, apoptosis, cell cycle regulation, and muscle contraction, among others. Furthermore, dysregulated calcium signaling has been implicated in various diseases, including certain neurological disorders and cancer. In this study, we aim to demonstrate the effects of native TBLF lectins and a recombinant lectin (rTBL-1) on calcium mobility in breast cancer cells (MCF-7) and non-cancerous cells (MCF-12F). Both TBLF and rTBL-1 increased intracellular calcium concentrations and mobilized calcium from intracellular stores in a concentration-dependent manner; however, the two cell lines exhibited differential responses. While MCF-12F cells restored cytoplasmic calcium concentration, MCF-7 cells maintained a high intracellular calcium concentration. This strongly suggests that lectins can elicit differential cellular responses in cancer and non-cancer cells due to variations in their intrinsic mechanisms of calcium homeostasis. Finally, we demonstrated that TBLF and rTBL-1 can differentially alter Metabolic Cellular Activity (MCA) as a direct measure of cell viability (CVi) in both cell lines. These findings strengthen the evidence of the therapeutic potential of Tepary bean lectins. Undoubtedly, further studies will be necessary to elucidate the mechanisms underlying their applications.
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Affiliation(s)
- Andrea Díaz-Betancourt
- Laboratorio de Biofísica de Membranas y Nanotecnología, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico; (A.D.-B.); (M.E.G.-C.); (V.M.-T.)
| | - María Elizabeth Galicia-Castillo
- Laboratorio de Biofísica de Membranas y Nanotecnología, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico; (A.D.-B.); (M.E.G.-C.); (V.M.-T.)
| | - Verónica Morales-Tlalpan
- Laboratorio de Biofísica de Membranas y Nanotecnología, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico; (A.D.-B.); (M.E.G.-C.); (V.M.-T.)
- Laboratorio Nacional de Visualización Científica Avanzada, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico
| | - Jorge Luis Chávez-Servín
- Laboratorio de Biología Celular y Molecular, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico;
| | - Alejandro Blanco-Labra
- Departamento de Biotecnología y Bioquímica, Centro de Investigación y Estudios Avanzados del IPN, Km. 9.6 Libramiento Norte, Carretera Irapuato-León, Irapuato 36824, Guanajuato, Mexico;
| | - Teresa García-Gasca
- Laboratorio de Biología Celular y Molecular, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico;
| | - Carlos Saldaña
- Laboratorio de Biofísica de Membranas y Nanotecnología, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico; (A.D.-B.); (M.E.G.-C.); (V.M.-T.)
- Laboratorio Nacional de Visualización Científica Avanzada, Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Av. De las Ciencias s/n, Juriquilla, Queretaro 76230, Queretaro, Mexico
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Li Q, Li H, Zhu R, Cho WCS, Yao X, Leung FP, Tse G, Leung LK, Wong WT. TRPV2 calcium channel promotes breast cancer progression potential by activating autophagy. Cancer Cell Int 2024; 24:324. [PMID: 39334351 PMCID: PMC11438410 DOI: 10.1186/s12935-024-03506-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Breast cancer, the most prevalent and aggressive tumor affecting women, requires identification of disease determinants to facilitate the development of effective therapeutic strategies. Transient receptor potential vanilloid 2 (TRPV2), an ion channel highly permeable for calcium (Ca2+), is implicated in physiological and pathological processes. Nevertheless, the role of TRPV2 in breast cancer remains poorly elucidated. In this study, we found high levels of TRPV2 expression associated with advanced malignancy, thereby suggesting its potential as a biomarker for breast cancer staging. We demonstrated that TRPV2 activation promotes breast cancer cell proliferation, migration, and invasion, while silencing of TRPV2 suppresses breast cancer progression, highlighting the oncogenic role of TRPV2. Moreover, we reveal that TRPV2 facilitates cancer progression by modulating the CaMKKβ/AMPK/ULK1-autophagic axis through mediating calcium influx, providing new insights into TRPV2 as a novel therapeutic target for breast cancer treatment.
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Affiliation(s)
- Qing Li
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Huixian Li
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, 999077, China
- State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Ruiwen Zhu
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, 999077, China
- State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - William Chi Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, 999077, China
| | - Xiaoqiang Yao
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Fung Ping Leung
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, 999077, China
- State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Gary Tse
- School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, 999077, China
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Lai Kwok Leung
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, 999077, China.
| | - Wing Tak Wong
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, 999077, China.
- State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, 999077, China.
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Busic-Pavlek I, Dumic-Cule I, Kovacevic L, Milosevic M, Delimar P, Korsa L, Marusic Z, Prutki M. Calcium-Sensing Receptor Expression in Breast Cancer. Int J Mol Sci 2023; 24:11678. [PMID: 37511437 PMCID: PMC10380606 DOI: 10.3390/ijms241411678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
The calcium-sensing receptor (CaSR) plays a crucial role in maintaining the balance of calcium in the body. Altered signaling through the CaSR has been linked to the development of various tumors, such as colorectal and breast tumors. This retrospective study enrolled 79 patients who underwent surgical removal of invasive breast carcinoma of no special type (NST) to explore the expression of the CaSR in breast cancer. The patients were categorized based on age, tumor size, hormone receptor status, HER2 status, Ki-67 proliferation index, tumor grade, and TNM staging. Immunohistochemistry was conducted on core needle biopsy samples to assess CaSR expression. The results revealed a positive correlation between CaSR expression and tumor size, regardless of the tumor surrogate subtype (p = 0.001). The expression of ER exhibited a negative correlation with CaSR expression (p = 0.033). In contrast, a positive correlation was observed between CaSR expression and the presence of HER2 receptors (p = 0.002). Increased CaSR expression was significantly associated with lymph node involvement and the presence of distant metastasis (p = 0.001 and p = 0.038, respectively). CaSR values were significantly higher in the patients with increased Ki-67 (p = 0.042). Collectively, higher CaSR expression in breast cancer could suggest a poor prognosis and treatment outcome regardless of the breast cancer subtype.
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Affiliation(s)
- Iva Busic-Pavlek
- Clinical Department of Diagnostic and Interventional Radiology, University Hospital Centre Split, Spinciceva 1, 21000 Split, Croatia
| | - Ivo Dumic-Cule
- Clinical Department of Diagnostic and Interventional Radiology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia
- Department of Nursing, University North, 104 Brigade 3, 42000 Varazdin, Croatia
| | - Lucija Kovacevic
- Clinical Department of Diagnostic and Interventional Radiology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia
| | - Milan Milosevic
- Department of Environmental Health and Occupational and Sports Medicine, Andrija Stampar School of Public Health, Rockfellerova 4, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, Salata 3, 10000 Zagreb, Croatia
| | - Petra Delimar
- Clinical Department of Diagnostic and Interventional Radiology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia
| | - Lea Korsa
- Clinical Department of Pathology and Cytology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia
| | - Zlatko Marusic
- Clinical Department of Pathology and Cytology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia
| | - Maja Prutki
- Clinical Department of Diagnostic and Interventional Radiology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, Salata 3, 10000 Zagreb, Croatia
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6
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Saldías MP, Cruz P, Silva I, Orellana-Serradell O, Lavanderos B, Maureira D, Pinto R, Cerda O. The Cytoplasmic Region of SARAF Reduces Triple-Negative Breast Cancer Metastasis through the Regulation of Store-Operated Calcium Entry. Int J Mol Sci 2023; 24:ijms24065306. [PMID: 36982380 PMCID: PMC10049260 DOI: 10.3390/ijms24065306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Triple-negative breast cancer has a poor prognosis and is non-responsive to first-line therapies; hence, new therapeutic strategies are needed. Enhanced store-operated Ca2+ entry (SOCE) has been widely described as a contributing factor to tumorigenic behavior in several tumor types, particularly in breast cancer cells. SOCE-associated regulatory factor (SARAF) acts as an inhibitor of the SOCE response and, therefore, can be a potential antitumor factor. Herein, we generated a C-terminal SARAF fragment to evaluate the effect of overexpression of this peptide on the malignancy of triple-negative breast cancer cell lines. Using both in vitro and in vivo approaches, we showed that overexpression of the C-terminal SARAF fragment reduced proliferation, cell migration, and the invasion of murine and human breast cancer cells by decreasing the SOCE response. Our data suggest that regulating the activity of the SOCE response via SARAF activity might constitute the basis for further alternative therapeutic strategies for triple-negative breast cancer.
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Affiliation(s)
- María Paz Saldías
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Pablo Cruz
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Ian Silva
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Octavio Orellana-Serradell
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Boris Lavanderos
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Diego Maureira
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Raquel Pinto
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Oscar Cerda
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago 8380453, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
- Correspondence: ; Tel.: +56-2-29786909
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The TRPC1 Channel Forms a PI3K/CaM Complex and Regulates Pancreatic Ductal Adenocarcinoma Cell Proliferation in a Ca2+-Independent Manner. Int J Mol Sci 2022; 23:ijms23147923. [PMID: 35887266 PMCID: PMC9323718 DOI: 10.3390/ijms23147923] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/15/2022] [Accepted: 07/17/2022] [Indexed: 02/04/2023] Open
Abstract
Dysregulation of the transient receptor canonical ion channel (TRPC1) has been found in several cancer types, yet the underlying molecular mechanisms through which TRPC1 impacts pancreatic ductal adenocarcinoma (PDAC) cell proliferation are incompletely understood. Here, we found that TRPC1 is upregulated in human PDAC tissue compared to adjacent pancreatic tissue and this higher expression correlates with low overall survival. TRPC1 is, as well, upregulated in the aggressive PDAC cell line PANC-1, compared to a duct-like cell line, and its knockdown (KD) reduced cell proliferation along with PANC-1 3D spheroid growth by arresting cells in the G1/S phase whilst decreasing cyclin A, CDK2, CDK6, and increasing p21CIP1 expression. In addition, the KD of TRPC1 neither affected Ca2+ influx nor store-operated Ca2+ entry (SOCE) and reduced cell proliferation independently of extracellular calcium. Interestingly, TRPC1 interacted with the PI3K-p85α subunit and calmodulin (CaM); both the CaM protein level and AKT phosphorylation were reduced upon TRPC1 KD. In conclusion, our results show that TRPC1 regulates PDAC cell proliferation and cell cycle progression by interacting with PI3K-p85α and CaM through a Ca2+-independent pathway.
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8
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Orduña-Castillo LB, Del-Río-Robles JE, García-Jiménez I, Zavala-Barrera C, Beltrán-Navarro YM, Hidalgo-Moyle JJ, Ramírez-Rangel I, Hernández-Bedolla MA, Reyes-Ibarra AP, Valadez-Sánchez M, Vázquez-Prado J, Reyes-Cruz G. Calcium sensing receptor stimulates breast cancer cell migration via the Gβγ-AKT-mTORC2 signaling pathway. J Cell Commun Signal 2021; 16:239-252. [PMID: 34854057 DOI: 10.1007/s12079-021-00662-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 11/21/2021] [Indexed: 10/19/2022] Open
Abstract
Calcium sensing receptor, a pleiotropic G protein coupled receptor, activates secretory pathways in cancer cells and putatively exacerbates their metastatic behavior. Here, we show that various CaSR mutants, identified in breast cancer patients, differ in their ability to stimulate Rac, a small Rho GTPase linked to cytoskeletal reorganization and cell protrusion, but are similarly active on the mitogenic ERK pathway. To investigate how CaSR activates Rac and drives cell migration, we used invasive MDA-MB-231 breast cancer cells. We revealed, by pharmacological and knockdown strategies, that CaSR activates Rac and cell migration via the Gβγ-PI3K-mTORC2 pathway. These findings further support current efforts to validate CaSR as a relevant therapeutic target in metastatic cancer.
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Affiliation(s)
- Lennis Beatriz Orduña-Castillo
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico
| | - Jorge Eduardo Del-Río-Robles
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico
| | - Irving García-Jiménez
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico
| | - César Zavala-Barrera
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico
| | | | - Joseline Janai Hidalgo-Moyle
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico
| | | | - Marco A Hernández-Bedolla
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico.,Licenciatura en Enfermería, Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Huejutla de Reyes, Hidalgo, México
| | - Alma P Reyes-Ibarra
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico
| | - Margarita Valadez-Sánchez
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico
| | | | - Guadalupe Reyes-Cruz
- Department of Cell Biology, CINVESTAV, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, CP 07360, Mexico City, Mexico.
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9
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Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression. Rev Physiol Biochem Pharmacol 2021; 182:39-84. [PMID: 34291319 DOI: 10.1007/112_2021_63] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Solid tumors, including breast carcinomas, are heterogeneous but typically characterized by elevated cellular turnover and metabolism, diffusion limitations based on the complex tumor architecture, and abnormal intra- and extracellular ion compositions particularly as regards acid-base equivalents. Carcinogenesis-related alterations in expression and function of ion channels and transporters, cellular energy levels, and organellar H+ sequestration further modify the acid-base composition within tumors and influence cancer cell functions, including cell proliferation, migration, and survival. Cancer cells defend their cytosolic pH and HCO3- concentrations better than normal cells when challenged with the marked deviations in extracellular H+, HCO3-, and lactate concentrations typical of the tumor microenvironment. Ionic gradients determine the driving forces for ion transporters and channels and influence the membrane potential. Cancer and stromal cells also sense abnormal ion concentrations via intra- and extracellular receptors that modify cancer progression and prognosis. With emphasis on breast cancer, the current review first addresses the altered ion composition and the changes in expression and functional activity of ion channels and transporters in solid cancer tissue. It then discusses how ion channels, transporters, and cellular sensors under influence of the acidic tumor microenvironment shape cancer development and progression and affect the potential of cancer therapies.
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10
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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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11
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Abstract
Ca2+ is a ubiquitous and dynamic second messenger molecule that is induced by many factors including receptor activation, environmental factors, and voltage, leading to pleiotropic effects on cell function including changes in migration, metabolism and transcription. As such, it is not surprising that aberrant regulation of Ca2+ signals can lead to pathological phenotypes, including cancer progression. However, given the highly context-specific nature of Ca2+-dependent changes in cell function, delineation of its role in cancer has been a challenge. Herein, we discuss the distinct roles of Ca2+ signaling within and between each type of cancer, including consideration of the potential of therapeutic strategies targeting these signaling pathways.
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Affiliation(s)
- Scott Gross
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Pranava Mallu
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Hinal Joshi
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Bryant Schultz
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Christina Go
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Jonathan Soboloff
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States; Department of Medical Genetics & Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.
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12
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Almasi S, El Hiani Y. Exploring the Therapeutic Potential of Membrane Transport Proteins: Focus on Cancer and Chemoresistance. Cancers (Basel) 2020; 12:cancers12061624. [PMID: 32575381 PMCID: PMC7353007 DOI: 10.3390/cancers12061624] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023] Open
Abstract
Improving the therapeutic efficacy of conventional anticancer drugs represents the best hope for cancer treatment. However, the shortage of druggable targets and the increasing development of anticancer drug resistance remain significant problems. Recently, membrane transport proteins have emerged as novel therapeutic targets for cancer treatment. These proteins are essential for a plethora of cell functions ranging from cell homeostasis to clinical drug toxicity. Furthermore, their association with carcinogenesis and chemoresistance has opened new vistas for pharmacology-based cancer research. This review provides a comprehensive update of our current knowledge on the functional expression profile of membrane transport proteins in cancer and chemoresistant tumours that may form the basis for new cancer treatment strategies.
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Affiliation(s)
- Shekoufeh Almasi
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON KIH 8M5, Canada;
| | - Yassine El Hiani
- Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Correspondence:
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13
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Elzamzamy OM, Penner R, Hazlehurst LA. The Role of TRPC1 in Modulating Cancer Progression. Cells 2020; 9:cells9020388. [PMID: 32046188 PMCID: PMC7072717 DOI: 10.3390/cells9020388] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/02/2020] [Accepted: 02/03/2020] [Indexed: 12/22/2022] Open
Abstract
Calcium ions (Ca2+) play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca2+-permeable ion channels are implicated in mediating Ca2+ signaling in cancer cells. In this review, we are focusing on TRPC1, a member of the TRP protein superfamily and a potential modulator of store-operated Ca2+ entry (SOCE) pathways. While TRPC1 is ubiquitously expressed in most tissues, its dysregulated activity may contribute to the hallmarks of various types of cancers, including breast cancer, pancreatic cancer, glioblastoma multiforme, lung cancer, hepatic cancer, multiple myeloma, and thyroid cancer. A range of pharmacological and genetic tools have been developed to address the functional role of TRPC1 in cancer. Interestingly, the unique role of TRPC1 has elevated this channel as a promising target for modulation both in terms of pharmacological inhibition leading to suppression of tumor growth and metastasis, as well as for agonistic strategies eliciting Ca2+ overload and cell death in aggressive metastatic tumor cells.
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Affiliation(s)
- Osama M Elzamzamy
- Clinical and Translational Sciences Institute, School of Medicine, West Virginia University, Morgantown, WV 26506, USA;
| | - Reinhold Penner
- The Queen’s Medical Center and University of Hawaii, Honolulu, HI 96813, USA;
| | - Lori A Hazlehurst
- Pharmaceutical Sciences, School of Pharmacy and WVU Cancer Institute, West Virginia University, Morganton, WV 26506, USA
- Correspondence: ; Tel.: +1-304-293-3398
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14
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Das S, Clézardin P, Kamel S, Brazier M, Mentaverri R. The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases. Front Oncol 2020; 10:69. [PMID: 32117726 PMCID: PMC7013091 DOI: 10.3389/fonc.2020.00069] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/15/2020] [Indexed: 12/11/2022] Open
Abstract
The Ca2+-sensing receptor (CaSR) is a class-C G protein-coupled receptor which plays a pivotal role in calciotropic processes, primarily in regulating parathyroid hormone secretion to maintain systemic calcium homeostasis. Among its non-calciotropic roles, where the CaSR sits at the intersection of myriad processes, it has steadily garnered attention as an oncogene or tumor suppressor in different organs. In maternal breast tissues the CaSR promotes lactation but in breast cancer it acts as an oncoprotein and has been shown to drive the pathogenesis of skeletal metastases from breast cancer. Even though research has made great strides in treating primary breast cancer, there is an unmet need when it comes to treatment of metastatic breast cancer. This review focuses on how the CaSR leads to the pathogenesis of breast cancer by contrasting its role in healthy tissues and tumorigenesis, and by drawing brief parallels with the tissues where it has been implicated as an oncogene. A class of compounds called calcilytics, which are CaSR antagonists, have also been surveyed in the instances where they have been used to target the receptor in cancerous tissues and constitute a proof of principle for repurposing them. Current clinical therapies for treating bone metastases from breast cancer are limited to targeting osteoclasts and a deeper understanding of the CaSR signaling nexus in this context can bolster them or lead to novel therapeutic interventions.
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Affiliation(s)
- Souvik Das
- MP3CV, EA7517, CURS, University of Picardie Jules Verne, Amiens, France
| | - Philippe Clézardin
- INSERM, Research Unit UMR_S1033, LyOS, Faculty of Medicine Lyon-Est, University of Lyon 1, Lyon, France
- Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Said Kamel
- MP3CV, EA7517, CURS, University of Picardie Jules Verne, Amiens, France
- Department of Biochemistry, Amiens-Picardie University Hospital, Amiens, France
- Faculty of Pharmacy, University of Picardie Jules Verne, Amiens, France
| | - Michel Brazier
- MP3CV, EA7517, CURS, University of Picardie Jules Verne, Amiens, France
- Department of Biochemistry, Amiens-Picardie University Hospital, Amiens, France
- Faculty of Pharmacy, University of Picardie Jules Verne, Amiens, France
| | - Romuald Mentaverri
- MP3CV, EA7517, CURS, University of Picardie Jules Verne, Amiens, France
- Department of Biochemistry, Amiens-Picardie University Hospital, Amiens, France
- Faculty of Pharmacy, University of Picardie Jules Verne, Amiens, France
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15
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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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16
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Eser Ocak P, Ocak U, Tang J, Zhang JH. The role of caveolin-1 in tumors of the brain - functional and clinical implications. Cell Oncol (Dordr) 2019; 42:423-447. [PMID: 30993541 DOI: 10.1007/s13402-019-00447-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Caveolin-1 (cav-1) is the major structural protein of caveolae, the flask-shaped invaginations of the plasma membrane mainly involved in cell signaling. Today, cav-1 is believed to play a role in a variety of disease processes including cancer, owing to the variations of its expression in association with tumor progression, invasive behavior, metastasis and therapy resistance. Since first detected in the brain, a number of studies has particularly focused on the role of cav-1 in the various steps of brain tumorigenesis. In this review, we discuss the different roles of cav-1 and its contributions to the molecular mechanisms underlying the pathobiology and natural behavior of brain tumors including glial, non-glial and metastatic subtypes. These contributions could be attributed to its co-localization with important players in tumorigenesis within the lipid-enriched domains of the plasma membrane. In that regard, the ability of cav-1 to interact with various cell signaling molecules as well as the impact of caveolae depletion on important pathways acting in brain tumor pathogenesis are noteworthy. We also discuss conversant causes hampering the treatment of malignant glial tumors such as limited transport of chemotherapeutics across the blood tumor barrier and resistance to chemoradiotherapy, by focusing on the molecular fundamentals involving cav-1 participation. CONCLUSIONS Cav-1 has the potential to pivot the molecular basis underlying the pathobiology of brain tumors, particularly the malignant glial subtype. In addition, the regulatory effect of cav-1-dependent and caveola-mediated transcellular transport on the permeability of the blood tumor barrier could be of benefit to overcome the restricted transport across brain barriers when applying chemotherapeutics. The association of cav-1 with tumors of the brain other than malignant gliomas deserves to be underlined, as well given the evidence suggesting its potential in predicting tumor grade and recurrence rates together with determining patient prognosis in oligodendrogliomas, ependymomas, meningiomas, vestibular schwannomas and brain metastases.
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Affiliation(s)
- Pinar Eser Ocak
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Umut Ocak
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Jiping Tang
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - John H Zhang
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Neurology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA.
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17
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Iamartino L, Elajnaf T, Kallay E, Schepelmann M. Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives. World J Gastroenterol 2018; 24:4119-4131. [PMID: 30271078 PMCID: PMC6158479 DOI: 10.3748/wjg.v24.i36.4119] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/11/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
The extracellular calcium-sensing receptor (CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the CaSR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitis-associated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.
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Affiliation(s)
- Luca Iamartino
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Taha Elajnaf
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Enikö Kallay
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Martin Schepelmann
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
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18
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Zhou W, Gong L, Li X, Wan Y, Wang X, Li H, Jiang B. Screening key candidate genes and pathways involved in insulinoma by microarray analysis. Medicine (Baltimore) 2018; 97:e10826. [PMID: 29851790 PMCID: PMC6392920 DOI: 10.1097/md.0000000000010826] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Insulinoma is a rare type tumor and its genetic features remain largely unknown. This study aimed to search for potential key genes and relevant enriched pathways of insulinoma.The gene expression data from GSE73338 were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified between insulinoma tissues and normal pancreas tissues, followed by pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. The expressions of candidate key genes were validated by quantitative real-time polymerase chain reaction (RT-PCR) in insulinoma tissues.A total of 1632 DEGs were obtained, including 1117 upregulated genes and 514 downregulated genes. Pathway enrichment results showed that upregulated DEGs were significantly implicated in insulin secretion, and downregulated DEGs were mainly enriched in pancreatic secretion. PPI network analysis revealed 7 hub genes with degrees more than 10, including GCG (glucagon), GCGR (glucagon receptor), PLCB1 (phospholipase C, beta 1), CASR (calcium sensing receptor), F2R (coagulation factor II thrombin receptor), GRM1 (glutamate metabotropic receptor 1), and GRM5 (glutamate metabotropic receptor 5). DEGs involved in the significant modules were enriched in calcium signaling pathway, protein ubiquitination, and platelet degranulation. Quantitative RT-PCR data confirmed that the expression trends of these hub genes were similar to the results of bioinformatic analysis.The present study demonstrated that candidate DEGs and enriched pathways were the potential critical molecule events involved in the development of insulinoma, and these findings were useful for better understanding of insulinoma genesis.
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Affiliation(s)
- Wuhua Zhou
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital
| | - Li Gong
- Department of Endocrinology, Taihe Hospital, Shiyan City, Hubei Province, China
| | - Xuefeng Li
- Department of Endocrinology, Taihe Hospital, Shiyan City, Hubei Province, China
| | - Yunyan Wan
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital
| | - Xiangfei Wang
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital
| | - Huili Li
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital
| | - Bin Jiang
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital
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19
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Tajbakhsh A, Pasdar A, Rezaee M, Fazeli M, Soleimanpour S, Hassanian SM, FarshchiyanYazdi Z, Younesi Rad T, Ferns GA, Avan A. The current status and perspectives regarding the clinical implication of intracellular calcium in breast cancer. J Cell Physiol 2018; 233:5623-5641. [PMID: 29150934 DOI: 10.1002/jcp.26277] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/06/2017] [Indexed: 12/20/2022]
Abstract
Calcium ions (Ca2+ ) act as second messengers in intracellular signaling. Ca2+ pumps, channels, sensors, and calcium binding proteins, regulate the concentrations of intracellular Ca2+ as a key regulator of important cellular processes such as gene expression, proliferation, differentiation, DNA repair, apoptosis, metastasis, and hormone secretion. Intracellular Ca2+ also influences the functions of several organelles, that include: the endoplasmic reticulum, mitochondria, the Golgi, and cell membrane both in normal and breast cancer cells. In breast cancer, the disruption of intracellular: Ca2+ homeostasis may cause tumor progression by affecting key factors/pathways including phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3), calmodulin (CaM), nuclear factor of activated T-cells (NFAT), calpain, calmodulin-dependent protein kinase II (CaMKII), mitogen-activated protein kinase (MAPK), epithelial-mesenchymal transition (EMT), vascular endothelial growth factor (VEGF), poly (ADP-Ribose) polymerase-1 (PARP1), estrogen, and estrogen receptor. Because the foregoing molecules play crucial roles in breast cancer, the factors/pathways influencing intracellular Ca2+ concentrations are putative targets for cancer treatment, using drugs such as Mephebrindole, Tilapia piscidin 4, Nifetepimine, Paricalcitol, and Prednisolone. We have explored the factors/pathways which are related to breast cancer and Ca2+ homeostasis and signaling in this review, and also discussed their potential as biomarkers for breast cancer staging, prognosis, and therapy.
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Affiliation(s)
- Amir Tajbakhsh
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Pasdar
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Division of Applied Medicine, Medical School, University of Aberdeen, Foresterhill, Aberdeen, UK.,Medical Genetics Research Centre, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Rezaee
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mostafa Fazeli
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra FarshchiyanYazdi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Laboratory Sciences, Faculty of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Tayebe Younesi Rad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Laboratory Sciences, Faculty of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Falmer, Brighton, Sussex, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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20
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The suppressive role of calcium sensing receptor in endometrial cancer. Sci Rep 2018; 8:1076. [PMID: 29348629 PMCID: PMC5773571 DOI: 10.1038/s41598-018-19286-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 09/18/2017] [Indexed: 12/14/2022] Open
Abstract
Studies have shown that calcium sensing receptor (CaSR) is involved in the progressions of several human cancers. However, the role of CaSR in endometrial cancer remains unknown. This study provides a preliminary analysis of the CaSR effect on endometrial cancer development. Ectopic CaSR expression by lentiviral transfection (CaSR-OV) in Ishikawa cells significantly increased intracellular calcium ([Ca2+]i) levels and cell apoptosis. E-cadherin and β-catenin expression and complex formation at the membrane were increased in CaSR-OV Ishikawa cells relative to control Ishikawa cells (vector). Furthermore, CaSR-OV Ishikawa cells showed a reduced invasive potential, which was attributed to E-cadherin/β-catenin complex formation. Moreover, a reduction in CaSR expression in endometrial cancer relative to normal specimens was evident by immunohistochemistry and was positively associated with E-cadherin, but not β-catenin, expression. Furthermore, VEGFR3 was significantly down-regulated in CaSR-OV Ishikawa cells. Additionally, an immunohistochemical analysis showed that VEGFR3 was significantly increased in endometrial cancer compared with the normal endometrium and was inversely correlated with CaSR expression. However, the CaSR knockdown produced the opposite effects. These findings suggest an inhibitory role for CaSR in endometrial cancer. Therefore, reduced CaSR expression may be a suitable explanation and valuable predictor for endometrial cancer progression.
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21
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Johnson RW, Sun Y, Ho PWM, Chan ASM, Johnson JA, Pavlos NJ, Sims NA, Martin TJ. Parathyroid Hormone-Related Protein Negatively Regulates Tumor Cell Dormancy Genes in a PTHR1/Cyclic AMP-Independent Manner. Front Endocrinol (Lausanne) 2018; 9:241. [PMID: 29867773 PMCID: PMC5964132 DOI: 10.3389/fendo.2018.00241] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 04/26/2018] [Indexed: 01/16/2023] Open
Abstract
Parathyroid hormone-related protein (PTHrP) expression in breast cancer is enriched in bone metastases compared to primary tumors. Human MCF7 breast cancer cells "home" to the bones of immune deficient mice following intracardiac inoculation, but do not grow well and stain negatively for Ki67, thus serving as a model of breast cancer dormancy in vivo. We have previously shown that PTHrP overexpression in MCF7 cells overcomes this dormant phenotype, causing them to grow as osteolytic deposits, and that PTHrP-overexpressing MCF7 cells showed significantly lower expression of genes associated with dormancy compared to vector controls. Since early work showed a lack of cyclic AMP (cAMP) response to parathyroid hormone (PTH) in MCF7 cells, and cAMP is activated by PTH/PTHrP receptor (PTHR1) signaling, we hypothesized that the effects of PTHrP on dormancy in MCF7 cells occur through non-canonical (i.e., PTHR1/cAMP-independent) signaling. The data presented here demonstrate the lack of cAMP response in MCF7 cells to full length PTHrP(1-141) and PTH(1-34) in a wide range of doses, while maintaining a response to three known activators of adenylyl cyclase: calcitonin, prostaglandin E2 (PGE2), and forskolin. PTHR1 mRNA was detectable in MCF7 cells and was found in eight other human breast and murine mammary carcinoma cell lines. Although PTHrP overexpression in MCF7 cells changed expression levels of many genes, RNAseq analysis revealed that PTHR1 was unaltered, and only 2/32 previous PTHR1/cAMP responsive genes were significantly upregulated. Instead, PTHrP overexpression in MCF7 cells resulted in significant enrichment of the calcium signaling pathway. We conclude that PTHR1 in MCF7 breast cancer cells is not functionally linked to activation of the cAMP pathway. Gene expression responses to PTHrP overexpression must, therefore, result from autocrine or intracrine actions of PTHrP independent of PTHR1, through signals emanating from other domains within the PTHrP molecule.
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Affiliation(s)
- Rachelle W. Johnson
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- *Correspondence: Rachelle W. Johnson,
| | - Yao Sun
- Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
- Department of Medicine at St. Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - Patricia W. M. Ho
- Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
| | - Audrey S. M. Chan
- Cellular Orthopaedic Laboratory, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Jasmine A. Johnson
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Nathan J. Pavlos
- Cellular Orthopaedic Laboratory, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Natalie A. Sims
- Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
- Department of Medicine at St. Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - T. John Martin
- Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
- Department of Medicine at St. Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
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22
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Faouzi M, Hague F, Geerts D, Ay AS, Potier-Cartereau M, Ahidouch A, Ouadid-Ahidouch H. Functional cooperation between KCa3.1 and TRPC1 channels in human breast cancer: Role in cell proliferation and patient prognosis. Oncotarget 2017; 7:36419-36435. [PMID: 27183905 PMCID: PMC5095010 DOI: 10.18632/oncotarget.9261] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 04/08/2016] [Indexed: 12/24/2022] Open
Abstract
Intracellular Ca2+ levels are important regulators of cell cycle and proliferation. We, and others, have previously reported the role of KCa3.1 (KCNN4) channels in regulating the membrane potential and the Ca2+ entry in association with cell proliferation. However, the relevance of KC3.1 channels in cancer prognosis as well as the molecular mechanism of Ca2+ entry triggered by their activation remain undetermined. Here, we show that RNAi-mediated knockdown of KCa3.1 and/or TRPC1 leads to a significant decrease in cell proliferation due to cell cycle arrest in the G1 phase. These results are consistent with the observed upregulation of both channels in synchronized cells at the end of G1 phase. Additionally, knockdown of TRPC1 suppressed the Ca2+ entry induced by 1-EBIO-mediated KCa3.1 activation, suggesting a functional cooperation between TRPC1 and KCa3.1 in the regulation of Ca2+ entry, possibly within lipid raft microdomains where these two channels seem to co-localize. We also show significant correlations between KCa3.1 mRNA expression and poor patient prognosis and unfavorable clinical breast cancer parameters by mining large datasets in the public domain. Together, these results highlight the importance of KCa3.1 in regulating the proliferative mechanisms in breast cancer cells as well as in providing a promising novel target in prognosis and therapy.
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Affiliation(s)
- Malika Faouzi
- University of Picardie Jules Verne, UFR of Sciences, EA4667 Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France.,Queen's Center for Biomedical Research, The Queen's Medical Center, Honolulu, HI 96813, USA
| | - Frederic Hague
- University of Picardie Jules Verne, UFR of Sciences, EA4667 Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France
| | - Dirk Geerts
- Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands
| | - Anne-Sophie Ay
- University of Picardie Jules Verne, UFR of Sciences, EA4667 Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France
| | - Marie Potier-Cartereau
- University of Picardie Jules Verne, UFR of Sciences, EA4667 Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France.,Inserm, UMR1069, Nutrition, Growth and Cancer, University of François Rabelais, Tours F-37032, France
| | - Ahmed Ahidouch
- University of Picardie Jules Verne, UFR of Sciences, EA4667 Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France
| | - Halima Ouadid-Ahidouch
- University of Picardie Jules Verne, UFR of Sciences, EA4667 Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France
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Wei L, Du Y, Jia L, Ma X, Chen Z, Lu J, Tian L, Duan Z, Dong F, Lv Z, Yao G, Fu R, Wang L. Therapeutic Effects of FK506 on IgA Nephropathy Rat. Kidney Blood Press Res 2017; 42:983-998. [PMID: 29179182 DOI: 10.1159/000485346] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 11/16/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS FK506 is an immunosuppressive drug and a calcineurin inhibitor that has been widely used in kidney disease in recent years. FK506 shows a wide range of biological and pharmaceutical effects; however, the mechanism of its anti- proliferative effect has not been well elucidated. An IgA nephropathy (IgAN) model was used to generate a mesangial cell proliferation model. This study aims to examine the effect of FK506 on IgAN rats and the underlying mechanisms. METHODS Hematuria, proteinuria and renal function were measured. To observe the pathological conditions, we performed HE (hematoxylin - eosin) and PAS (periodic acid - schiff) staining. Transcription and protein expression levels were detected by qRT - PCR (quantitative real-time polymerase chain reaction) and Wb (western blotting). The location and semi-quantitative expression levels of TRPCs, CaN (Calcineurin) and α-SMA were examined by IHC (Immunohistochemical staining). RESULTS We found that FK506 could improve hematuria, proteinuria and renal function, especially in the HF (high-dose FK506) groups. Renal pathological changes were ameliorated in the treatment groups. FK506 could significantly decrease TRPCs, CaN, phosphorylation of ERK1/2 and α-SMA expression. CONCLUSION Taken together, these results suggest that the therapeutic effect of FK506 on IgAN might be partially associated with the down-regulated expression of TRPC channels, CaN and phosphorylation of ERK1/2.
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Affiliation(s)
- Linting Wei
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Du
- Department of Nephrology, the First Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Lining Jia
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaotao Ma
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhao Chen
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiamei Lu
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lifang Tian
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhaoyang Duan
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fengming Dong
- Department of Nephrology, Jiangsu Taizhou People's Hospital, Taizhou, China
| | - Zhian Lv
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ganglian Yao
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rongguo Fu
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Li Wang
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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GPCRs and EGFR – Cross-talk of membrane receptors in cancer. Bioorg Med Chem Lett 2017; 27:3611-3620. [PMID: 28705643 DOI: 10.1016/j.bmcl.2017.07.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 06/28/2017] [Accepted: 07/01/2017] [Indexed: 12/20/2022]
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Non-linear actions of physiological agents: Finite disarrangements elicit fitness benefits. Redox Biol 2017; 13:235-243. [PMID: 28595161 PMCID: PMC5460745 DOI: 10.1016/j.redox.2017.05.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 05/11/2017] [Indexed: 12/16/2022] Open
Abstract
Finite disarrangements of important (vital) physiological agents and nutrients can induce plethora of beneficial effects, exceeding mere attenuation of the specific stress. Such response to disrupted homeostasis appears to be universally conserved among species. The underlying mechanism of improved fitness and longevity, when physiological agents act outside their normal range is similar to hormesis, a phenomenon whereby toxins elicit beneficial effects at low doses. Due to similarity with such non-linear response to toxins described with J-shaped curve, we have coined a new term “mirror J-shaped curves” for non-linear response to finite disarrangement of physiological agents. Examples from the clinical trials and basic research are provided, along with the unifying mechanisms that tie classical non-linear response to toxins with the non-linear response to physiological agents (glucose, oxygen, osmolarity, thermal energy, calcium, body mass, calorie intake and exercise). Reactive oxygen species and cytosolic calcium seem to be common triggers of signaling pathways that result in these beneficial effects. Awareness of such phenomena and exploring underlying mechanisms can help physicians in their everyday practice. It can also benefit researchers when designing studies and interpreting growing number of scientific data showing non-linear responses to physiological agents.
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26
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Cui C, Merritt R, Fu L, Pan Z. Targeting calcium signaling in cancer therapy. Acta Pharm Sin B 2017; 7:3-17. [PMID: 28119804 PMCID: PMC5237760 DOI: 10.1016/j.apsb.2016.11.001] [Citation(s) in RCA: 407] [Impact Index Per Article: 50.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 10/28/2016] [Indexed: 12/15/2022] Open
Abstract
The intracellular calcium ions (Ca2+) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca2+ homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Ca2+ signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca2+ channels, transporters and Ca2+-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca2+ channels/transporters or Ca2+-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Ca2+ signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca2+ channels or transporters.
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Key Words
- 20-GPPD, 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol
- Apoptosis
- CBD, cannabidiol
- CBG, cannabigerol
- CPZ, capsazepine
- CRAC, Ca2+ release-activated Ca2+ channel
- CTL, cytotoxic T cells
- CYP3A4, cytochrome P450 3A4
- Ca2+ channels
- CaM, calmodulin
- CaMKII, calmodulin-dependent protein kinase II
- Cancer therapy
- Cell proliferation
- Channel blockers;
- ER/SR, endoplasmic/sarcoplasmic reticulum
- HCX, H+/Ca2+ exchangers
- IP3, inositol 1,4,5-trisphosphate
- IP3R (1, 2, 3), IP3 receptor (type 1, type 2, type 3)
- MCU, mitochondrial Ca2+ uniporter
- MCUR1, MCU uniporter regulator 1
- MICU (1, 2, 3), mitochondrial calcium uptake (type 1, type 2, type 3)
- MLCK, myosin light-chain kinase
- Migration
- NCX, Na+/Ca2+ exchanger
- NF-κB, nuclear factor-κB
- NFAT, nuclear factor of activated T cells
- NSCLC, non-small cell lung cancer
- OSCC, oral squamous cell carcinoma cells
- PKC, protein kinase C
- PM, plasma membrane
- PMCA, plasma membrane Ca2+-ATPase
- PTP, permeability transition pore
- ROS, reactive oxygen species
- RyR, ryanodine receptor
- SERCA, SR/ER Ca2+-ATPase
- SOCE, store-operated Ca2+ entry
- SPCA, secretory pathway Ca2+-ATPase
- Store-operated Ca2+ entry
- TEA, tetraethylammonium
- TG, thapsigargin
- TPC2, two-pore channel 2
- TRIM, 1-(2-(trifluoromethyl) phenyl) imidazole
- TRP (A, C, M, ML, N, P, V), transient receptor potential (ankyrin, canonical, melastatin, mucolipin, no mechanoreceptor potential C, polycystic, vanilloid)
- VGCC, voltage-gated Ca2+ channel
- mAb, monoclonal antibody
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Affiliation(s)
- Chaochu Cui
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Department of Surgery, Division of Thoracic Surgery, The Ohio State University, Columbus, OH 43210, USA
| | - Robert Merritt
- Department of Surgery, Division of Thoracic Surgery, The Ohio State University, Columbus, OH 43210, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zui Pan
- Department of Surgery, Division of Thoracic Surgery, The Ohio State University, Columbus, OH 43210, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA
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Schaar A, Sukumaran P, Sun Y, Dhasarathy A, Singh BB. TRPC1-STIM1 activation modulates transforming growth factor β-induced epithelial-to-mesenchymal transition. Oncotarget 2016; 7:80554-80567. [PMID: 27793015 PMCID: PMC5348340 DOI: 10.18632/oncotarget.12895] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 10/19/2016] [Indexed: 12/21/2022] Open
Abstract
Activation of Epithelial-to-Mesenchymal Transition (EMT) is important for tumor metastasis. Although growth factors such as TGFβ and EGF have been shown to induce EMT in breast epithelial cells, the mechanism resulting in migration is not well understood. Herein, we provide evidence that Ca2+ entry into the cell, especially upon store-depletion, plays an important role in TGFβ-induced EMT by promoting cellular migration and potentially leading to metastasis. The increased migration by TGFβ in non-cancerous cells was due to the loss of E-cadherin along with a subsequent increase in N-cadherin levels. Importantly, TGFβ-treatment increases store-mediated Ca2+ entry, which was essential for the activation of calpain leading to the loss of E-cadherin and MMP activation. Inhibition of Ca2+ entry by using Ca2+ channel blocker SKF-96365, significantly decreased Ca2+ entry, decreased TGFβ-induced calpain activation, and suppressed the loss of E-cadherin along with inhibiting cell migration. Furthermore, TRPC1 function as an endogenous Ca2+ entry channel and silencing of either TRPC1 or its activator, STIM1, significantly decreased TGFβ induced Ca2+ entry, inhibited TGFβ-mediated calpain activation and cell migration. In contrast, overexpression of TRPC1 showed increased Ca2+ entry and promoted TGFβ-mediated cell migration. Moreover, increased TRPC1 expression was observed in ductal carcinoma cells. Together these results suggest that disrupting Ca2+ influx via TRPC1/STIM1 mechanism reduces calpain activity, which could restore intercellular junction proteins thereby inhibiting EMT induced motility.
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Affiliation(s)
- Anne Schaar
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201, USA
| | - Pramod Sukumaran
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201, USA
| | - Yuyang Sun
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201, USA
| | - Archana Dhasarathy
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201, USA
| | - Brij B Singh
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201, USA
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Bernichtein S, Pigat N, Barry Delongchamps N, Boutillon F, Verkarre V, Camparo P, Reyes-Gomez E, Méjean A, Oudard SM, Lepicard EM, Viltard M, Souberbielle JC, Friedlander G, Capiod T, Goffin V. Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation. Cancer Res 2016; 77:355-365. [PMID: 27879271 DOI: 10.1158/0008-5472.can-16-0687] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 10/28/2016] [Accepted: 10/31/2016] [Indexed: 01/29/2023]
Abstract
Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca2+ resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355-65. ©2016 AACR.
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Affiliation(s)
- Sophie Bernichtein
- Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France
| | - Natascha Pigat
- Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France
| | - Nicolas Barry Delongchamps
- Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.,Urology Department, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Florence Boutillon
- Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France
| | - Virginie Verkarre
- Pathology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | | | - Edouard Reyes-Gomez
- Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'anatomo-cytopathologie, Inserm, IMRB U955-E10, Université Paris-Est, Maisons-Alfort, Paris, France
| | - Arnaud Méjean
- Urology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Stéphane M Oudard
- Medical Oncology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Eve M Lepicard
- Institute for European Expertise in Physiology, Paris, France
| | - Mélanie Viltard
- Institute for European Expertise in Physiology, Paris, France
| | - Jean-Claude Souberbielle
- Physiology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Gérard Friedlander
- Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France
| | - Thierry Capiod
- Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France
| | - Vincent Goffin
- Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.
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Kim W, Wysolmerski JJ. Calcium-Sensing Receptor in Breast Physiology and Cancer. Front Physiol 2016; 7:440. [PMID: 27746743 PMCID: PMC5043011 DOI: 10.3389/fphys.2016.00440] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 09/16/2016] [Indexed: 12/31/2022] Open
Abstract
The calcium-sensing receptor (CaSR) is expressed in normal breast epithelial cells and in breast cancer cells. During lactation, activation of the CaSR in mammary epithelial cells increases calcium transport into milk and inhibits parathyroid hormone-related protein (PTHrP) secretion into milk and into the circulation. The ability to sense changes in extracellular calcium allows the lactating breast to actively participate in the regulation of systemic calcium and bone metabolism, and to coordinate calcium usage with calcium availability during milk production. Interestingly, as compared to normal breast cells, in breast cancer cells, the regulation of PTHrP secretion by the CaSR becomes rewired due to a switch in its G-protein usage such that activation of the CaSR increases instead of decreases PTHrP production. In normal cells the CaSR couples to Gαi to inhibit cAMP and PTHrP production, whereas in breast cancer cells, it couples to Gαs to stimulate cAMP and PTHrP production. Activation of the CaSR on breast cancer cells regulates breast cancer cell proliferation, death and migration, in part, by stimulating PTHrP production. In this article, we discuss the biology of the CaSR in the normal breast and in breast cancer, and review recent findings suggesting that the CaSR activates a nuclear pathway of PTHrP action that stimulates cellular proliferation and inhibits cell death, helping cancer cells adapt to elevated extracellular calcium levels. Understanding the diverse actions mediated by the CaSR may help us better understand lactation physiology, breast cancer progression and osteolytic bone metastases.
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Affiliation(s)
- Wonnam Kim
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine New Haven, CT, USA
| | - John J Wysolmerski
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine New Haven, CT, USA
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Kim W, Takyar FM, Swan K, Jeong J, VanHouten J, Sullivan C, Dann P, Yu H, Fiaschi-Taesch N, Chang W, Wysolmerski J. Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone-Related Protein. Cancer Res 2016; 76:5348-60. [PMID: 27450451 DOI: 10.1158/0008-5472.can-15-2614] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 06/17/2016] [Indexed: 12/21/2022]
Abstract
Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth, and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo Tissue-specific disruption of the casr gene in mammary epithelial cells in MMTV-PymT mice reduced tumor PTHrP expression and inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27(kip1) levels and prevented nuclear accumulation of the proapoptotic factor apoptosis inducing factor. Taken together, our findings suggest that CaSR-PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression. Cancer Res; 76(18); 5348-60. ©2016 AACR.
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Affiliation(s)
- Wonnam Kim
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut
| | - Farzin M Takyar
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut
| | - Karena Swan
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut
| | - Jaekwang Jeong
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut
| | - Joshua VanHouten
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut
| | - Catherine Sullivan
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut
| | - Pamela Dann
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut
| | - Herbert Yu
- Cancer Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii School of Medicine, Honolulu, Hawaii
| | - Nathalie Fiaschi-Taesch
- Section of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Wenhan Chang
- Endocrine Unit, San Francisco and Veteran Affairs Medical Center, University of California, San Francisco, California
| | - John Wysolmerski
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
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The calcium-sensing receptor and the hallmarks of cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1398-407. [DOI: 10.1016/j.bbamcr.2015.11.017] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 11/17/2015] [Accepted: 11/18/2015] [Indexed: 02/07/2023]
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Extracellular Calcium Has Multiple Targets to Control Cell Proliferation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 898:133-56. [DOI: 10.1007/978-3-319-26974-0_7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Fielden MR, Dean C, Black K, Sawant SG, Subramanian R, Tomlinson JE, Walter S, Zimmermann C, Griggs MW, McKeon ME, Lewis EM, Beevers C, Pyrah I. Nonclinical Safety Profile of Etelcalcetide, a Novel Peptide Calcimimetic for the Treatment of Secondary Hyperparathyroidism. Int J Toxicol 2016; 35:294-308. [DOI: 10.1177/1091581816633407] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Etelcalcetide is a novel d-amino acid peptide that functions as an allosteric activator of the calcium-sensing receptor and is being developed as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis. To support clinical development and marketing authorization, a comprehensive nonclinical safety package was generated. Primary adverse effects included hypocalcemia, tremoring, and convulsions. Other adverse effects were considered sequelae of stress associated with hypocalcemia. Cardiovascular safety evaluations in the dog revealed an anticipated prolongation of the corrected QT interval that was related to reductions in serum calcium. Etelcalcetide did not affect the human ether-a-go-go gene ion channel current. Etelcalcetide was mutagenic in some strains of Salmonella, however, based on the negative results in 2 in vitro and 2 in vivo mammalian genotoxicity assays, including a 28-day Muta mouse study, etelcalcetide is considered nongenotoxic. Further support for a lack of genotoxicity was provided due to the fact that etelcalcetide was not carcinogenic in a 6-month transgenic rasH2 mouse model or a 2-year study in rats. There were no effects on fertility, embryo–fetal development, and prenatal and postnatal development. All of the adverse effects observed in both rat and dog were considered directly or secondarily related to the pharmacologic activity of etelcalcetide and the expected sequelae associated with dose-related reductions in serum calcium due to suppression of parathyroid hormone secretion. These nonclinical data indicate no safety signal of concern for human risk beyond that associated with hypocalcemia and associated QT prolongation.
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Affiliation(s)
- Mark R. Fielden
- Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA
| | - Charles Dean
- Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA
| | - Kurt Black
- Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA
| | - Satin G. Sawant
- Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA
| | - Raju Subramanian
- Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, CA, USA
| | | | - Sarah Walter
- Cardiometabolic Disorders, Amgen Inc, Thousand Oaks, CA, USA
| | - Cameron Zimmermann
- Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA
| | | | | | | | | | - Ian Pyrah
- Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA
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Jeong S, Kim JH, Kim MG, Han N, Kim IW, Kim T, Oh JM. Genetic polymorphisms of CASR and cancer risk: evidence from meta-analysis and HuGE review. Onco Targets Ther 2016; 9:655-69. [PMID: 26929638 PMCID: PMC4755434 DOI: 10.2147/ott.s97602] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background CASR gene appears to be involved in cancer biology and physiology. However, a number of studies investigating CASR polymorphisms and cancer risks have presented inconclusive results. Thus, a systematic review and a meta-analysis of the effect of CASR polymorphisms on several cancer risks were performed to suggest a statistical evidence for the association of CASR polymorphisms with cancer risks. Methods MEDLINE, EMBASE, Web of Science, Scopus, and the HuGE databases were searched. Nineteen articles of case–control and cohort studies were included for the final analysis. Results The colorectal cancer risk was reduced in proximal (odds ratio [OR] =0.679, P=0.001) and distal (OR =0.753, P=0.026) colon sites with GG genotype of CASR rs1042636 and increased in distal colon site (OR =1.418, P=0.039) with GG genotype of rs1801726 by additive genetic model. The rs17251221 demonstrated noticeable associations that carrying a homozygote variant increases breast and prostate cancer risk considerably. Conclusion The significant association of CASR polymorphisms with several cancer risks was observed in this review. In particular, the act of CASR polymorphisms as a tumor suppressor or an oncogene differs by cancer site and can be the research target for tumorigenesis.
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Affiliation(s)
- Sohyun Jeong
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Jae Hyun Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Myeong Gyu Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Nayoung Han
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - In-Wha Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Therasa Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Jung Mi Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
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Chen J, Luan Y, Yu R, Zhang Z, Zhang J, Wang W. Transient receptor potential (TRP) channels, promising potential diagnostic and therapeutic tools for cancer. Biosci Trends 2014; 8:1-10. [PMID: 24647107 DOI: 10.5582/bst.8.1] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Despite the advances in detection of and therapies for various tumors, high rates of treatment failure and mortality still exist throughout the world. These high rates are mainly due to the powerful capability of tumor cells to proliferate and migrate. Recent studies regarding the transient receptor potential (TRP) have indicated that TRP channels are associated with tumors and that TRP channels might represent potential targets for cancer treatment. TRP channels are important calcium-selective ion channels in many different tissues and cell types in mammals and are crucial regulators of calcium and sodium. TRP were first discovered in the photoreceptors of Drosophila with gene defects or mutations. TRP channels can be divided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), TRPA (ankyrin transmembrane protein), and TRPN (NomPC-like). TRPC proteins are conserved across organisms since they are most homologous to Drosophila TRP. TRP superfamilies have been linked to many physiological and pathological functions, including cell differentiation, proliferation, apoptosis, and ion homeostasis. This review focuses on the properties of TRP in oncogenesis, cancer proliferation, and cell migration.
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Affiliation(s)
- Jianpeng Chen
- Department of Oncology, Provincial Hospital Affiliated with Shandong University
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Guéguinou M, Gambade A, Félix R, Chantôme A, Fourbon Y, Bougnoux P, Weber G, Potier-Cartereau M, Vandier C. Lipid rafts, KCa/ClCa/Ca2+ channel complexes and EGFR signaling: Novel targets to reduce tumor development by lipids? BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2014; 1848:2603-20. [PMID: 25450343 DOI: 10.1016/j.bbamem.2014.10.036] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/15/2014] [Accepted: 10/22/2014] [Indexed: 12/29/2022]
Abstract
Membrane lipid rafts are distinct plasma membrane nanodomains that are enriched with cholesterol, sphingolipids and gangliosides, with occasional presence of saturated fatty acids and phospholipids containing saturated acyl chains. It is well known that they organize receptors (such as Epithelial Growth Factor Receptor), ion channels and their downstream acting molecules to regulate intracellular signaling pathways. Among them are Ca2+ signaling pathways, which are modified in tumor cells and inhibited upon membrane raft disruption. In addition to protein components, lipids from rafts also contribute to the organization and function of Ca2+ signaling microdomains. This article aims to focus on the lipid raft KCa/ClCa/Ca2+ channel complexes that regulate Ca2+ and EGFR signaling in cancer cells, and discusses the potential modification of these complexes by lipids as a novel therapeutic approach in tumor development. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
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Affiliation(s)
- Maxime Guéguinou
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Audrey Gambade
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Romain Félix
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Aurélie Chantôme
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Yann Fourbon
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Philippe Bougnoux
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France; Centre HS Kaplan, CHRU Tours, Tours F-37032, France
| | - Günther Weber
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Marie Potier-Cartereau
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Christophe Vandier
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France.
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Li H, Sun Y, Zheng H, Li L, Yu Q, Yao X. Parathyroid hormone-related protein overexpression protects goat mammary gland epithelial cells from calcium-sensing receptor activation-induced apoptosis. Mol Biol Rep 2014; 42:233-43. [DOI: 10.1007/s11033-014-3763-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 09/20/2014] [Indexed: 12/12/2022]
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Wang D, Li X, Liu J, Li J, Li LJ, Qiu MX. Effects of TRPC6 on invasibility of low-differentiated prostate cancer cells. ASIAN PAC J TROP MED 2014; 7:44-7. [PMID: 24418082 DOI: 10.1016/s1995-7645(13)60190-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 06/15/2013] [Accepted: 07/15/2013] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE To study the expression of TRPC6 among prostate cancer cells, establish high expression cell lines of TRPC6, and to provide potential cell mode for prostate cancer oncogenesis and development. METHODS Occurrence and development of prostate cancer cells, PC3, PC-3 m DU145, 22 rv1, LNCaP and normal prostate epithelial cells in the PrEC TRPC6 expression level were detected by QPCR method. Calcium phosphate transfection method was used to package retrovirus pLEGFP-N1-TRPC6 and pLEGFP-N1-vector and infect the prostate cancer cells, a stable high expression of TRPC6 prostate cancer cells. Sable cell lines of TRPC6, matrix metalloproteinase (MMP) 2, MMP9 expression was detected by QPCR and Western blot. Change of cell invasion ability was detected by Transwell. RESULTS The expression level of prostate cancer cells TRPC6 were higher than control group PrEC cells. Among TPRC6 the expression of cell line PC 3 transfer potential wre the lowest, and high transfer cell line PC-3M express was the highest. Real-time fluorescent quantitative PCR and western blot results showed that after filter, the seventh generation of cell TRPC6 protein and mRNA expression levels were higher than the control group obviously. Transwell experimental results showed that the overexpression of TRPC6 could promote the invasion ability of PC3 prostate cancer cells. CONCLUSIONS TRPC6 expressed in prostate cancer cells is in disorder, and its action may be associated with the invasion and metastasis of prostate cancer cells; successful establishment of stable high expression of TRPC6 prostate cancer cells primarily confirm the invasion-trigger ability of TRPC6 on prostate cancer, and lay down the Foundation for exploring the TRPC6's role in the occurrence and development of prostate cancer mechanism.
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Affiliation(s)
- Dong Wang
- Department of Urology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China.
| | - Xiang Li
- Department of Urology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Liu
- Department of Urology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Jun Li
- Department of Urology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Li-Jun Li
- Department of Urology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Ming-Xing Qiu
- Department of Urology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China
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Feng J, Xu X, Li B, Brown E, Farris AB, Sun SY, Yang JJ. Prostate cancer metastatic to bone has higher expression of the calcium-sensing receptor (CaSR) than primary prostate cancer. ACTA ACUST UNITED AC 2014; 1. [PMID: 26065011 DOI: 10.14800/rci.270] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The calcium-sensing receptor (CaSR) is the principal regulator of the secretion of parathyroid hormone and plays key roles in extracellular calcium (Ca2+o) homeostasis. It is also thought to participate in the development of cancer, especially bony metastases of breast and prostate cancer. However, the expression of CaSR has not been systematically analyzed in prostate cancer from patients with or without bony metastases. By comparing human prostate cancer tissue sections in microarrays, we found that the CaSR was expressed in both normal prostate and primary prostate cancer as assessed by immunohistochemistry (IHC). We used two methods to analyze the expression level of CaSR. One was the pathological score read by a pathologist, the other was the positivity% obtained from the Aperio positive pixel count algorithm. Both of the methods gave consistent results. Metastatic prostate cancer tissue obtained from bone had higher CaSR expression than primary prostate cancer (P <0.05). The expression of CaSR in primary prostate cancers of patients with metastases to tissues other than bone was not different from that in primary prostate cancer of patients with or without bony metastases (P >0.05). The expression of CaSR in cancer tissue was not associated with the stage or status of differentiation of the cancer. These results suggest that CaSR may have a role in promoting bony metastasis of prostate cancer, hence raising the possibility of reducing the risk of such metastases with CaSR-based therapeutics.
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Affiliation(s)
- Jie Feng
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303
| | - Xiaojun Xu
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303
| | - Bo Li
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322
| | - Edward Brown
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115
| | - Alton B Farris
- Department of Pathology, Emory University, Atlanta, GA 30322
| | - Shi-Yong Sun
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322
| | - Jenny J Yang
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30303
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40
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Prognostic significance of calcium-sensing receptor in breast cancer. Tumour Biol 2014; 35:5709-15. [DOI: 10.1007/s13277-014-1756-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Accepted: 02/13/2014] [Indexed: 10/25/2022] Open
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Borowiec AS, Bidaux G, Pigat N, Goffin V, Bernichtein S, Capiod T. Calcium channels, external calcium concentration and cell proliferation. Eur J Pharmacol 2013; 739:19-25. [PMID: 24291106 DOI: 10.1016/j.ejphar.2013.10.072] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 09/28/2013] [Accepted: 10/17/2013] [Indexed: 11/16/2022]
Abstract
Evidence for a role for calcium channel proteins in cell proliferation is numerous suggesting that calcium influx is essential in this physiological process. Several studies in the past thirty years have demonstrated that calcium channel expression levels are determinant in cell proliferation. Voltage-gated, store-operated, second messengers and receptor-operated calcium channels have been associated to cell proliferation. However, the relationship between calcium influx and cell proliferation can be uncoupled in transformed and cancer cells, resulting in an external calcium-independent proliferation. Thus, protein expression could be more important than channel function to trigger cell proliferation suggesting that additional channel functions may be responsible to reconcile calcium channel expression and cell proliferation. When needed, external calcium concentration is obviously important for calcium channel function but it also regulates calcium sensing receptor (CaSR) activity. CaSR can up- or down-regulate cell proliferation depending on physiological conditions. CaSR sensitivity to external calcium is within the 0.5 to 5 mM range and therefore, the role of these receptors in cell proliferation must be taken into account. We therefore suggest here that cell proliferation rates could depend on the relative balance between calcium influx and CaSR activation.
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Affiliation(s)
| | - Gabriel Bidaux
- INSERM U1003, LabEx ICST, Université Lille 1, Villeneuve d'Ascq F-59655, France
| | - Natascha Pigat
- INSERM U845, Research Center Growth and Signalling Research Center, Paris Descartes University, Sorbonne Paris Cité, Faculty of Medicine, Bâtiment Leriche, 96 rue Didot, Paris F-75993, France
| | - Vincent Goffin
- INSERM U845, Research Center Growth and Signalling Research Center, Paris Descartes University, Sorbonne Paris Cité, Faculty of Medicine, Bâtiment Leriche, 96 rue Didot, Paris F-75993, France
| | - Sophie Bernichtein
- INSERM U845, Research Center Growth and Signalling Research Center, Paris Descartes University, Sorbonne Paris Cité, Faculty of Medicine, Bâtiment Leriche, 96 rue Didot, Paris F-75993, France
| | - Thierry Capiod
- INSERM U845, Research Center Growth and Signalling Research Center, Paris Descartes University, Sorbonne Paris Cité, Faculty of Medicine, Bâtiment Leriche, 96 rue Didot, Paris F-75993, France.
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Cross BM, Breitwieser GE, Reinhardt TA, Rao R. Cellular calcium dynamics in lactation and breast cancer: from physiology to pathology. Am J Physiol Cell Physiol 2013; 306:C515-26. [PMID: 24225884 DOI: 10.1152/ajpcell.00330.2013] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Breast cancer is the second leading cause of cancer mortality in women, estimated at nearly 40,000 deaths and more than 230,000 new cases diagnosed in the U.S. this year alone. One of the defining characteristics of breast cancer is the radiographic presence of microcalcifications. These palpable mineral precipitates are commonly found in the breast after formation of a tumor. Since free Ca(2+) plays a crucial role as a second messenger inside cells, we hypothesize that these chelated precipitates may be a result of dysregulated Ca(2+) secretion associated with tumorigenesis. Transient and sustained elevations of intracellular Ca(2+) regulate cell proliferation, apoptosis and cell migration, and offer numerous therapeutic possibilities in controlling tumor growth and metastasis. During lactation, a developmentally determined program of gene expression controls the massive transcellular mobilization of Ca(2+) from the blood into milk by the coordinated action of calcium transporters, including pumps, channels, sensors and buffers, in a functional module that we term CALTRANS. Here we assess the evidence implicating genes that regulate free and buffered Ca(2+) in normal breast epithelium and cancer cells and discuss mechanisms that are likely to contribute to the pathological characteristics of breast cancer.
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Affiliation(s)
- Brandie M Cross
- Department of Physiology, The Johns Hopkins University, Baltimore, Maryland
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43
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Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Sildenafil inhibits hypoxia-induced transient receptor potential canonical protein expression in pulmonary arterial smooth muscle via cGMP-PKG-PPARγ axis. Am J Respir Cell Mol Biol 2013; 49:231-40. [PMID: 23526219 DOI: 10.1165/rcmb.2012-0185oc] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Transient receptor potential canonical (TRPC) proteins play important roles in chronically hypoxic pulmonary hypertension (CHPH). Previous results indicated that sildenafil inhibited TRPC1 and TRPC6 expression in rat distal pulmonary arteries (PAs). However, the underlying mechanisms remain unknown. We undertook this study to investigate the downstream signaling of sildenafil's regulation on TRPC1 and TRPC6 expression in pulmonary arterial smooth muscle cells (PASMCs). Hypoxia-exposed rats (10% O2 for 21 d) and rat distal PASMCs (4% O2 for 60 h) were taken as models to mimic CHPH. Real-time PCR, Western blotting, and Fura-2-based fluorescent microscopy were performed for mRNA, protein, and Ca(2+) measurements, respectively. The cellular cyclic guanosine monophosphate (cGMP) analogue 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate sodium salt (CPT-cGMP) (100 μM) inhibited TRPC1 and TRPC6 expression, store-operated Ca(2+) entry (SOCE), and the proliferation and migration of PASMCs exposed to prolonged hypoxia. The inhibition of CPT-cGMP on TRPC1 and TRPC6 expression in PASMCs was relieved by either the inhibition or knockdown of cGMP-dependent protein kinase (PKG) and peroxisome proliferator-activated receptor γ (PPARγ) expression. Under hypoxic conditions, CPT-cGMP increased PPARγ expression. This increase was abolished by the PKG antagonists Rp8 or KT5823. PPARγ agonist GW1929 significantly decreased TRPC1 and TRPC6 expression in PASMCs. Moreover, hypoxia exposure decreased, whereas sildenafil treatment increased, PKG and PPARγ expression in PASMCs ex vivo, and in rat distal PAs in vivo. The suppressive effects of sildenafil on TRPC1 and TRPC6 in rat distal PAs and on the hemodynamic parameters of CHPH were inhibited by treatment with the PPARγ antagonist T0070907. We conclude that sildenafil inhibits TRPC1 and TRPC6 expression in PASMCs via cGMP-PKG-PPARγ-dependent signaling during CHPH.
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Affiliation(s)
- Jian Wang
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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Li X, Lu W, Fu X, Zhang Y, Yang K, Zhong N, Ran P, Wang J. BMP4 increases canonical transient receptor potential protein expression by activating p38 MAPK and ERK1/2 signaling pathways in pulmonary arterial smooth muscle cells. Am J Respir Cell Mol Biol 2013; 49:212-20. [PMID: 23526217 DOI: 10.1165/rcmb.2012-0051oc] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Abnormal bone morphogenetic protein (BMP) signaling has been implicated in the pathogenesis of pulmonary hypertension. We previously found that BMP4 elevated basal intracellular Ca(2+) ([Ca(2+)]i) concentrations in distal pulmonary arterial smooth muscle cells (PASMCs), attributable in large part to enhanced store-operated Ca(2+) entry through store-operated Ca(2+) channels (SOCCs). Moreover, BMP4 up-regulated the expression of canonical transient receptor potential (TRPC) proteins thought to compose SOCCs. The present study investigated the signaling pathways through which BMP4 regulates TRPC expression and basal [Ca(2+)]i in distal PASMCs. Real-time quantitative PCR was used for the measurement of mRNA, Western blotting was used for the measurement of protein, and fluorescent microscopic for [Ca(2+)]i was used to determine the involvement of p38 and extracellular regulated kinase (ERK)-1/2 mitogen-activated protein kinase (MAPK) signaling in BMP4-induced TRPC expression and the elevation of [Ca(2+)]i in PASMCs. We found that the treatment of BMP4 led to the activation of both p38 MAPK and ERK1/2 in rat distal PASMCs. The induction of TRPC1, TRPC4, and TRPC6 expression, and the increases of [Ca(2+)]i caused by BMP4 in distal PASMCs, were inhibited by treatment with either SB203580 (10 μM), the selective inhibitor for p38 activation, or the specific p38 small interfering RNA (siRNA). Similarly, those responses induced by BMP4 were also abolished by treatment with PD98059 (5 μM), the selective inhibitor of ERK1/2, or by the knockdown of ERK1/2 using its specific siRNA. These results indicate that BMP4 participates in the regulation of Ca(2+) signaling in PASMCs by modulating TRPC channel expression via activating p38 and ERK1/2 MAPK pathways.
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Affiliation(s)
- Xiaoyan Li
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
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Conigrave AD, Ward DT. Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab 2013; 27:315-31. [PMID: 23856262 DOI: 10.1016/j.beem.2013.05.010] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
In this article we consider the mechanisms by which the calcium-sensing receptor (CaSR) induces its cellular responses via the control (activation or inhibition) of signaling pathways. We consider key features of CaSR-mediated signaling including its control of the heterotrimeric G-proteins Gq/11, Gi/o and G12/13 and the downstream consequences recognizing that very few CaSR-mediated cell phenomena have been fully described. We also consider the manner in which the CaSR contributes to the formation of specific signaling scaffolds via peptide recognition sequences in its intracellular C-terminal along with the origins of its high level of cooperativity, particularly for Ca(2+)o, and its remarkable resistance to desensitization. We also consider the nature of the mechanisms by which the CaSR controls oscillatory and sustained Ca(2+)i mobilizing responses and inhibits or elevates cyclic adenosine monophosphate (cAMP) levels dependent on the cellular and signaling context. Finally, we consider the diversity of the receptor's ligands, ligand binding sites and broader compartment-dependent physiological roles leading to the identification of pronounced ligand-biased signaling for agonists including Sr(2+) and modulators including l-amino acids and the clinically effective calcimimetic cinacalcet. We note the implications of these findings for the development of new designer drugs that might target the CaSR in pathophysiological contexts beyond those established for the treatment of disorders of calcium metabolism.
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Affiliation(s)
- Arthur D Conigrave
- School of Molecular Bioscience, University of Sydney, NSW 2006, Australia.
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46
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Abstract
Normal breast epithelial cells and breast cancer cells express the calcium-sensing receptor (CaSR), the master regulator of systemic calcium metabolism. During lactation, activation of the CaSR in mammary epithelial cells downregulates parathyroid hormone-related protein (PTHrP) levels in milk and in the circulation, and increases calcium transport into milk. In contrast, in breast cancer cells the CaSR upregulates PTHrP production. A switch in G-protein usage underlies the opposing effects of the CaSR on PTHrP expression in normal and malignant breast cells. During lactation, the CaSR in normal breast cells coordinates a feedback loop that matches the transport of calcium into milk and maternal calcium metabolism to the supply of calcium. A switch in CaSR G-protein usage during malignant transformation converts this feedback loop into a feed-forward cycle in breast cancer cells that may promote the growth of osteolytic skeletal metastases.
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Affiliation(s)
- Joshua N Vanhouten
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, TAC S131, Box 208020, New Haven, CT, USA.
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47
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Motiani RK, Stolwijk JA, Newton RL, Zhang X, Trebak M. Emerging roles of Orai3 in pathophysiology. Channels (Austin) 2013; 7:392-401. [PMID: 23695829 DOI: 10.4161/chan.24960] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Calcium (Ca(2+)) is a ubiquitous second messenger that regulates a plethora of physiological functions. Deregulation of calcium homeostasis has been reported in a wide variety of pathological conditions including cardiovascular disorders, cancer and neurodegenerative diseases. One of the most ubiquitous pathways involved in regulated Ca(2+) influx into cells is the store-operated Ca(2+) entry (SOCE) pathway. In 2006, Orai1 was identified as the channel protein that mediates SOCE in immune cells. Orai1 has two mammalian homologs, Orai2 and Orai3. Although Orai1 has been the most widely studied Orai isoform, Orai3 has recently received significant attention. Under native conditions, Orai3 was demonstrated to be an important component of store-independent arachidonate-regulated Ca(2+) (ARC) entry in HEK293 cells, and more recently of a store-independent leukotrieneC4-regulated Ca(2+) (LRC) entry pathway in vascular smooth muscle cells. Recent studies have shown upregulation of Orai3 in estrogen receptor-expressing breast cancers and a critical role for Orai3 in breast cancer development in immune-compromised mice. Orai3 upregulation was also shown to contribute to vascular smooth muscle remodeling and neointimal hyperplasia caused by vascular injury. Furthermore, Orai3 has been shown to contribute to proliferation of effector T-lymphocytes under oxidative stress. In this review, we will discuss the role of Orai3 in reported pathophysiological conditions and will contribute ideas on the potential role of Orai3 in native Ca(2+) signaling pathways and human disease.
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Affiliation(s)
- Rajender K Motiani
- Nanobioscience Constellation; College of Nanoscale Science and Engineering (CNSE); University at Albany; State University of New York; Albany, NY USA; DST-INSPIRE Faculty; Institute of Genomics and Integrative Biology (IGIB); New Delhi, India
| | - Judith A Stolwijk
- Nanobioscience Constellation; College of Nanoscale Science and Engineering (CNSE); University at Albany; State University of New York; Albany, NY USA
| | - Rachel L Newton
- Nanobioscience Constellation; College of Nanoscale Science and Engineering (CNSE); University at Albany; State University of New York; Albany, NY USA
| | - Xuexin Zhang
- Nanobioscience Constellation; College of Nanoscale Science and Engineering (CNSE); University at Albany; State University of New York; Albany, NY USA
| | - Mohamed Trebak
- Nanobioscience Constellation; College of Nanoscale Science and Engineering (CNSE); University at Albany; State University of New York; Albany, NY USA
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TRP channels: diagnostic markers and therapeutic targets for breast cancer? Trends Mol Med 2013; 19:117-24. [DOI: 10.1016/j.molmed.2012.11.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Revised: 09/25/2012] [Accepted: 11/13/2012] [Indexed: 01/22/2023]
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49
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Calcium sensing receptor signalling in physiology and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2012; 1833:1732-44. [PMID: 23267858 DOI: 10.1016/j.bbamcr.2012.12.011] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 12/10/2012] [Accepted: 12/12/2012] [Indexed: 12/13/2022]
Abstract
The calcium sensing receptor (CaSR) is a class C G-protein-coupled receptor that is crucial for the feedback regulation of extracellular free ionised calcium homeostasis. While extracellular calcium (Ca(2+)o) is considered the primary physiological ligand, the CaSR is activated physiologically by a plethora of molecules including polyamines and l-amino acids. Activation of the CaSR by different ligands has the ability to stabilise unique conformations of the receptor, which may lead to preferential coupling of different G proteins; a phenomenon termed 'ligand-biased signalling'. While mutations of the CaSR are currently not linked with any malignancies, altered CaSR expression and function are associated with cancer progression. Interestingly, the CaSR appears to act both as a tumour suppressor and an oncogene, depending on the pathophysiology involved. Reduced expression of the CaSR occurs in both parathyroid and colon cancers, leading to loss of the growth suppressing effect of high Ca(2+)o. On the other hand, activation of the CaSR might facilitate metastasis to bone in breast and prostate cancer. A deeper understanding of the mechanisms driving CaSR signalling in different tissues, aided by a systems biology approach, will be instrumental in developing novel drugs that target the CaSR or its ligands in cancer. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.
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50
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Tajeddine N, Gailly P. TRPC1 protein channel is major regulator of epidermal growth factor receptor signaling. J Biol Chem 2012; 287:16146-57. [PMID: 22451676 DOI: 10.1074/jbc.m112.340034] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
TRP channels have been associated with cell proliferation and aggressiveness in several cancers. In particular, TRPC1 regulates cell proliferation and motility, two processes underlying cancer progression. We and others have described the mechanisms of TRPC1-dependent cell migration. However, the involvement of TRPC1 in cell proliferation remains unexplained. In this study, we show that siRNA-mediated TRPC1 depletion in non small cell lung carcinoma cell lines induced G(0)/G(1) cell cycle arrest resulting in dramatic decrease in cell growth. The expression of cyclins D1 and D3 was reduced after TRPC1 knockdown, pointing out the role of TRPC1 in G(1)/S transition. This was associated with a decreased phosphorylation and activation of EGFR and with a subsequent disruption of PI3K/Akt and MAPK downstream pathways. Stimulation of EGFR by its natural ligand, EGF, induced Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry through TRPC1. Ca(2+) entry through TRPC1 conversely activated EGFR, suggesting that TRPC1 is a component of a Ca(2+)-dependent amplification of EGF-dependent cell proliferation.
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Affiliation(s)
- Nicolas Tajeddine
- Laboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, Belgium
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