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1
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Kong F, Chen Y, Liu D, Gao H, Yi Q, Zhang M, Li D. Marvelon suppresses MC38 tumor growth and promotes anti-tumor immunity. Mol Immunol 2025; 182:20-29. [PMID: 40158361 DOI: 10.1016/j.molimm.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 03/15/2025] [Accepted: 03/16/2025] [Indexed: 04/02/2025]
Abstract
Colorectal cancer is a prevalent and deadly malignancy globally, posing an important challenge due to its heterogeneity and treatment resistance. Although oral contraceptives have been shown to reduce the incidence of colorectal cancer, their impact on the anti-tumor effect of CD8+ T cells remains unclear. Here we show that the contraceptive Marvelon plays an important role in anti-MC38 tumor immunity. The contraceptive Marvelon significantly inhibits MC38 tumor growth in vivo. Marvelon treatment promotes IFN-γ expression in CD8+ tumor infiltrating lymphocytes, but shows dispensable impact on their exhausted profile. By further investigating the effects of Marvelon's primary components, Ethinylestradiol and Desogestrel, we reveal that Ethinylestradiol enhances IFN-γ production in Type 1 Cytotoxic T (Tc1) cells and significantly inhibits the viability of MC38 tumor cells, whereas Desogestrel exhibits minimal effects. This study not only redefines the role of oral contraceptives but also provides valuable insights for the development of novel immunotherapeutic strategies.
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Affiliation(s)
- Fandi Kong
- Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Yongyan Chen
- Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Dantong Liu
- Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Hongying Gao
- Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Qiaoru Yi
- Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Mengjuan Zhang
- Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
| | - Dan Li
- Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
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2
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Mariana SM, Brenda RP, Heriberto PG, Cristina L, David B, Guadalupe ÁL. GPER1 activation by estrogenic compounds in the inflammatory profile of breast cancer cells. J Steroid Biochem Mol Biol 2025; 245:106639. [PMID: 39571822 DOI: 10.1016/j.jsbmb.2024.106639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/28/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
Breast cancer (BC) is the most frequent female neoplasm worldwide. Its establishment and development have been related to inflammatory cytokine expression. Steroid hormones such as estradiol (E2) can regulate proinflammatory cytokine secretion through interaction with its nuclear receptors. However, little is known regarding the activation of its membrane estrogen receptor (GPER1) and the inflammatory cytokine environment in BC. We have studied the synthesis and biological effects of molecules analogs to E2 for hormone replacement therapy (HRT), such as pentolame. Nevertheless, its interaction with GPER1 and the modulation of inflammatory cytokines in different BC types has been barely studied and deserves deeper investigation. In this research, the role of GPER1 in the proliferation and modulation of inflammatory cytokines involved in carcinogenesis and metastatic processes in different BC cell lines was assessed by binding to various compounds. To achieve this goal, the presence of GPER1 was identified in different BC cell lines. Subsequently, cell proliferation after exposure to E2, pentolame and GPER1 agonist, G1, was subsequently determined alone or in combination with the GPER1 antagonist, G15. Finally, the pro-inflammatory cytokine secretion derived from the supernatants of BC cells exposed to the previous treatments was also assessed. Interestingly, GPER1 activation or inhibition has significant effects on the cytokine regulation associated with invasion in BC. Notably, pentolame did not induce cell proliferation or increase the proinflammatory cytokine expression compared to E2 in BC cell lines. In addition, pentolame did not induce the presence of the cell adhesion molecule PECAM-1. In contrast, E2 treatment weakly induced the expression of PECAM-1 in MCF-7 and HCC1937 cells, and G1 treatment showed this effect only in MCF-7 cells. The results suggest that GPER1 might be a significant inflammatory modulator with angiogenic-related effects in BC cells. In addition, pentolame might represent an HRT alternative in patients with BC predisposition.
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Affiliation(s)
- Segovia-Mendoza Mariana
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
| | - Reyes-Plata Brenda
- Facultad de Estudios Superiores Zaragoza. Universidad Nacional Autónoma de México,Ciudad de México, Mexico
| | - Prado-Garcia Heriberto
- Laboratorio de Onco-Inmunobiología, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, "Ismael Cosio Villegas" Calzada de Tlalpan 4502, Col. Sección XVI, Ciudad de México 14080, Mexico
| | - Lemini Cristina
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Barrera David
- Departamento de Biología de la Reproducción "Dr. Carlos Gual Castro", Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Col. Belisario Domínguez, Sección XVI, Ciudad de México 14080, Mexico
| | - Ángeles-López Guadalupe
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
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3
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Abbas MA, Al-Kabariti AY, Sutton C. Comprehensive understanding of the role of GPER in estrogen receptor-alpha negative breast cancer. J Steroid Biochem Mol Biol 2024; 241:106523. [PMID: 38636681 DOI: 10.1016/j.jsbmb.2024.106523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 11/01/2023] [Accepted: 04/14/2024] [Indexed: 04/20/2024]
Abstract
G protein-coupled estrogen receptor (GPER) plays a prominent role in facilitating the rapid, non-genomic signaling of estrogens in breast cancer cells. Herein, a comprehensive overview of the role of GPER in ER-ɑ-negative breast cancer is provided. Activation of GPER affected proliferation, metastasis and epithelial mesenchymal transition in ER-ɑ negative breast cancer cells. Clinical studies have demonstrated that GPER positivity was strongly correlated with larger tumor size and advanced clinical stage, suggesting that GPER/ERK signaling may play a role in promoting tumor progression. Strong evidence existed that environmental contaminants like bisphenol A have a carcinogenic potential mediated by GPER activation. The complexity of the cross talk between GPER and other receptors including ER-β, ER-α36, Estrogen-related receptor α (ERRα) and androgen receptor has been discussed. The potential utility of small molecules and phytoestrogens targeting GPER, adds valuable insights into its therapeutic potential. This review holds promises in advancing our understanding of GPER role in ER-ɑ-negative breast cancer. Overall, the consequences of GPER activation are still an area of active research and the implication are not entirely clear.
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Affiliation(s)
- Manal A Abbas
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan; Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman 19328, Jordan
| | - Aya Y Al-Kabariti
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan; Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman 19328, Jordan.
| | - Chris Sutton
- School of Chemistry and Biosciences, University of Bradford, Bradford BD7 1DP, UK
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4
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Prossnitz ER, Barton M. The G protein-coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol 2023:10.1038/s41574-023-00822-7. [PMID: 37193881 DOI: 10.1038/s41574-023-00822-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/28/2023] [Indexed: 05/18/2023]
Abstract
Oestrogens and their receptors contribute broadly to physiology and diseases. In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.
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Affiliation(s)
- Eric R Prossnitz
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
| | - Matthias Barton
- Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
- Andreas Grüntzig Foundation, Zürich, Switzerland.
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5
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Arterburn JB, Prossnitz ER. G Protein-Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications. Annu Rev Pharmacol Toxicol 2023; 63:295-320. [PMID: 36662583 PMCID: PMC10153636 DOI: 10.1146/annurev-pharmtox-031122-121944] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and β), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein-coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.
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Affiliation(s)
- Jeffrey B Arterburn
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, USA
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA;
| | - Eric R Prossnitz
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA;
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, and Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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6
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Qiu YA, Xiong J, Yu T. Role of G Protein-Coupled Estrogen Receptor in Digestive System Carcinomas: A Minireview. Onco Targets Ther 2021; 14:2611-2622. [PMID: 33888991 PMCID: PMC8055353 DOI: 10.2147/ott.s291896] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/16/2021] [Indexed: 12/14/2022] Open
Abstract
Digestive system carcinomas are one of the leading causes of cancer-related deaths worldwide. G protein-coupled estrogen receptor (GPER), a novel estrogen receptor, has been recognized as an important mediator in numerous cancer types. Recently, the function and clinical significance of GPER in digestive system carcinomas has been a subject of interest. Increasing evidence has revealed that GPER plays an important role as a potential biomarker in digestive system carcinomas. This work summarizes the recent literature and focuses on the emerging functional role of GPER in digestive system carcinomas, including gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. The potential application of GPER in novel strategies for the diagnosis and treatment of digestive system carcinomas is discussed and highlighted.
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Affiliation(s)
- Yu-An Qiu
- Department of Critical Care Medicine, Jiangxi Cancer Hospital, Nanchang University Cancer Hospital, Nanchang, 330029, People's Republic of China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Tenghua Yu
- Department of Breast Surgery, Jiangxi Cancer Hospital, Nanchang University Cancer Hospital, Nanchang, 330029, People's Republic of China
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Pepermans RA, Sharma G, Prossnitz ER. G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives. Cells 2021; 10:cells10030672. [PMID: 33802978 PMCID: PMC8002620 DOI: 10.3390/cells10030672] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.
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Affiliation(s)
- Richard A. Pepermans
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (R.A.P.); (G.S.)
| | - Geetanjali Sharma
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (R.A.P.); (G.S.)
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Eric R. Prossnitz
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (R.A.P.); (G.S.)
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
- Correspondence: ; Tel.: +1-505-272-5647
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8
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Jacenik D, Beswick EJ, Krajewska WM, Prossnitz ER. G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis. World J Gastroenterol 2019; 25:4092-4104. [PMID: 31435166 PMCID: PMC6700692 DOI: 10.3748/wjg.v25.i30.4092] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/03/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023] Open
Abstract
Estrogens play important roles in the development and progression of multiple tumor types. Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast, endometrium and ovary, but also in the development of colorectal cancer (CRC). The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptors α and β, as well as the membrane-bound G protein-coupled estrogen receptor (GPER). The roles of GPER in CRC development and progression, however, remain poorly understood. Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases, such as Crohn’s disease and ulcerative colitis. GPER is also involved in cell cycle regulation, endoplasmic reticulum stress, proliferation, apoptosis, vascularization, cell migration, and the regulation of fatty acid and estrogen metabolism in CRC cells. Thus, multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis. In this review, we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, Poland
- Department of Internal Medicine, School of Medicine, and UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, United States
| | - Ellen J Beswick
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84132, United States
| | - Wanda M Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, Poland
| | - Eric R Prossnitz
- Department of Internal Medicine, School of Medicine, and UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, United States
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9
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Zheng Y, Houston KD. Glucose-dependent GPER1 expression modulates tamoxifen-induced IGFBP-1 accumulation. J Mol Endocrinol 2019; 63:103-112. [PMID: 31242463 PMCID: PMC6598863 DOI: 10.1530/jme-18-0253] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 05/29/2019] [Indexed: 12/22/2022]
Abstract
G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMP-activated protein kinase (AMPK)-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased GPER1-mediated and tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] may increase breast cancer cell sensitivity to tamoxifen. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that modifies one aspect tamoxifen action in breast cancer cells.
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Affiliation(s)
- Yan Zheng
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, USA
| | - Kevin D Houston
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, USA
- Correspondence should be addressed to K D Houston:
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10
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Jacenik D, Cygankiewicz AI, Krajewska WM. The G protein-coupled estrogen receptor as a modulator of neoplastic transformation. Mol Cell Endocrinol 2016; 429:10-8. [PMID: 27107933 DOI: 10.1016/j.mce.2016.04.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 04/07/2016] [Accepted: 04/19/2016] [Indexed: 12/18/2022]
Abstract
Estrogens play a crucial role in the regulation of physiological and pathophysiological processes. These hormones act through specific receptors, most notably the canonical estrogen receptors α and β (ERα and ERβ) and their truncated forms as well as the G protein-coupled estrogen receptor (GPER). Several studies have shown that GPER is expressed in many normal and cancer cells, including those of the breast, endometrium, ovary, testis and lung. Hormonal imbalance is one possible cause of cancer development. An accumulating body of evidence indicates that GPER is involved in the regulation of cancer cell proliferation, migration and invasion, it may act as a mediator of microRNA, and is believed to modulate the inflammation associated with neoplastic transformation. Furthermore, used in various treatment regimens anti-estrogens such as tamoxifen, raloxifen and fulvestrant (ICI 182.780), antagonists/modulators of canonical estrogen receptors, were found to be GPER agonists. This review presents the current knowledge about the potential role of GPER in neoplastic transformation.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
| | - Adam I Cygankiewicz
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
| | - Wanda M Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
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11
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Zhou K, Sun P, Zhang Y, You X, Li P, Wang T. Estrogen stimulated migration and invasion of estrogen receptor-negative breast cancer cells involves an ezrin-dependent crosstalk between G protein-coupled receptor 30 and estrogen receptor beta signaling. Steroids 2016; 111:113-120. [PMID: 26850467 DOI: 10.1016/j.steroids.2016.01.021] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 01/26/2016] [Accepted: 01/28/2016] [Indexed: 11/16/2022]
Abstract
Estrogen mediates important cellular activities in estrogen receptor negative (ER-) breast cancer cells via membrane associated G protein-coupled receptor 30 (GPR30). However, the biological role and mechanism of estrogen action on cell motility and invasion in this aggressive kind of tumors remains poorly understood. We showed here that treatment with 17β-estradiol (E2) in ER-negative cancer cells resulted in ezrin-dependent cytoskeleton rearrangement and elicited a stimulatory effect on cell migration and invasion. Mechanistically, E2 induced ezrin activation was mediated by distinct mechanisms in different cell contexts. In SK-BR-3 cells with a high GPR30/ERβ ratio, silencing of GPR30 was able to abolish E2 induced ERK1/2, AKT phosphorylation and ezrin activation, whereas in MDA-MB-231 cells with low GPR30/ERβ ratio, E2 stimulated ezrin activation was mediated by the ERβ/PI3K/AKT signaling pathway. Importantly, we showed that activation of GPR30 signaling significantly prevents ERβ activation induced ezrin phosphorylation, cell migration and invasion, indicating an antagonist effect between GPR30 and ERβ signaling in MDA-MB-231 cells. These findings highlight the important interplay between different estrogen receptors in estrogen induced cell motility and invasiveness in ER-negative breast cancer cells.
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Affiliation(s)
- Kewen Zhou
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, People's Republic of China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou 510080, People's Republic of China
| | - Peng Sun
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, People's Republic of China; Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510080, People's Republic of China
| | - Yaxing Zhang
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, People's Republic of China
| | - Xinchao You
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, People's Republic of China
| | - Ping Li
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, People's Republic of China
| | - Tinghuai Wang
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, People's Republic of China.
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12
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Function of G-Protein-Coupled Estrogen Receptor-1 in Reproductive System Tumors. J Immunol Res 2016; 2016:7128702. [PMID: 27314054 PMCID: PMC4903118 DOI: 10.1155/2016/7128702] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 04/08/2016] [Accepted: 05/08/2016] [Indexed: 01/13/2023] Open
Abstract
The G-protein-coupled estrogen receptor-1 (GPER-1), also known as GPR30, is a novel estrogen receptor mediating estrogen receptor signaling in multiple cell types. The progress of estrogen-related cancer is promoted by GPER-1 activation through mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), and phospholipase C (PLC) signaling pathways. However, this promoting effect of GPER-1 is nonclassic estrogen receptor (ER) dependent manner. In addition, clinical evidences revealed that GPER-1 is associated with estrogen resistance in estrogen-related cancer patients. These give a hint that GPER-1 may be a novel therapeutic target for the estrogen-related cancers. However, preclinical studies also found that GPER-1 activation of its special agonist G-1 inhibits cancer cell proliferation. This review aims to summarize the characteristics and complex functions of GPER-1 in cancers.
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Grassi D, Ghorbanpoor S, Acaz-Fonseca E, Ruiz-Palmero I, Garcia-Segura LM. The Selective Estrogen Receptor Modulator Raloxifene Regulates Arginine-Vasopressin Gene Expression in Human Female Neuroblastoma Cells Through G Protein-Coupled Estrogen Receptor and ERK Signaling. Endocrinology 2015. [PMID: 26200092 DOI: 10.1210/en.2014-2010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The selective estrogen receptor modulator raloxifene reduces blood pressure in hypertensive postmenopausal women. In the present study we have explored whether raloxifene regulates gene expression of arginine vasopressin (AVP), which is involved in the pathogenesis of hypertension. The effect of raloxifene was assessed in human female SH-SY5Y neuroblastoma cells, which have been recently identified as a suitable cellular model to study the estrogenic regulation of AVP. Raloxifene, within a concentration ranging from 10(-10) M to 10(-6) M, decreased the mRNA levels of AVP in SH-SY5Y cells with maximal effect at 10(-7) M. This effect of raloxifene was imitated by an agonist (±)-1-[(3aR*,4S*,9bS*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone of G protein-coupled estrogen receptor-1 (GPER) and blocked by an antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline of GPER and by GPER silencing. Raloxifene induced a time-dependent increase in the level of phosphorylated ERK1 and ERK2, by a mechanism blocked by the GPER antagonist. The treatment of SH-SY5Y cells with either a MAPK/ERK kinase 1/2-specific inhibitor (1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadine) or a protein kinase C inhibitor (sotrastaurin) blocked the effects of raloxifene on the phosphorylation of ERK1/2 and the regulation of AVP mRNA levels. These results reveal a mechanism mediating the regulation of AVP expression by raloxifene, involving the activation of GPER, which in turn activates protein kinase C, MAPK/ERK kinase, and ERK. The regulation of AVP by raloxifene and GPER may have implications for the treatment of blood hypertension(.).
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Affiliation(s)
- Daniela Grassi
- Instituto Cajal (D.G., S.G., E.A.-F., I.R.P., L.M.G.-S.), Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain; Institute of Anatomy and Cell Biology (D.G.), Department of Molecular Embryology, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany; and Department of Cell and Molecular Biology (S.G.), School of Biology, College of Science, University of Tehran, 14155-6455 Tehran, Iran
| | - Samar Ghorbanpoor
- Instituto Cajal (D.G., S.G., E.A.-F., I.R.P., L.M.G.-S.), Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain; Institute of Anatomy and Cell Biology (D.G.), Department of Molecular Embryology, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany; and Department of Cell and Molecular Biology (S.G.), School of Biology, College of Science, University of Tehran, 14155-6455 Tehran, Iran
| | - Estefania Acaz-Fonseca
- Instituto Cajal (D.G., S.G., E.A.-F., I.R.P., L.M.G.-S.), Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain; Institute of Anatomy and Cell Biology (D.G.), Department of Molecular Embryology, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany; and Department of Cell and Molecular Biology (S.G.), School of Biology, College of Science, University of Tehran, 14155-6455 Tehran, Iran
| | - Isabel Ruiz-Palmero
- Instituto Cajal (D.G., S.G., E.A.-F., I.R.P., L.M.G.-S.), Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain; Institute of Anatomy and Cell Biology (D.G.), Department of Molecular Embryology, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany; and Department of Cell and Molecular Biology (S.G.), School of Biology, College of Science, University of Tehran, 14155-6455 Tehran, Iran
| | - Luis M Garcia-Segura
- Instituto Cajal (D.G., S.G., E.A.-F., I.R.P., L.M.G.-S.), Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain; Institute of Anatomy and Cell Biology (D.G.), Department of Molecular Embryology, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany; and Department of Cell and Molecular Biology (S.G.), School of Biology, College of Science, University of Tehran, 14155-6455 Tehran, Iran
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14
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Ge LC, Wang HS. A commentary on "Involvement of activating ERK1/2 trough G protein coupled receptor 30 and estrogen receptor α/β in low doses of bisphenol A promoting growth of Sertoli TM4 cells". Toxicol Lett 2015; 240:236-7. [PMID: 26427357 DOI: 10.1016/j.toxlet.2015.09.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Li-Chen Ge
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Hong-Sheng Wang
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
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15
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Chimento A, Sirianni R, Casaburi I, Zolea F, Rizza P, Avena P, Malivindi R, De Luca A, Campana C, Martire E, Domanico F, Fallo F, Carpinelli G, Cerquetti L, Amendola D, Stigliano A, Pezzi V. GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo. Oncotarget 2015; 6:19190-203. [PMID: 26131713 PMCID: PMC4662484 DOI: 10.18632/oncotarget.4241] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 05/23/2015] [Indexed: 12/26/2022] Open
Abstract
We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC.
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Affiliation(s)
- Adele Chimento
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Rosa Sirianni
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Ivan Casaburi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Fabiana Zolea
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Pietro Rizza
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Paola Avena
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Rocco Malivindi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Arianna De Luca
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Carmela Campana
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Emilia Martire
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Francesco Domanico
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Francesco Fallo
- Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Giulia Carpinelli
- Department of Cell Biology and Neurosciences, National Institute of Health, Rome, Italy
| | - Lidia Cerquetti
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Faculty of Medicine and Psychology, Rome, Italy
| | | | - Antonio Stigliano
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Faculty of Medicine and Psychology, Rome, Italy
| | - Vincenzo Pezzi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
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16
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Ribeiro MPC, Santos AE, Custódio JBA. Rethinking tamoxifen in the management of melanoma: New answers for an old question. Eur J Pharmacol 2015; 764:372-378. [PMID: 26165763 DOI: 10.1016/j.ejphar.2015.07.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 06/29/2015] [Accepted: 07/08/2015] [Indexed: 12/18/2022]
Abstract
The use of the antiestrogen tamoxifen in melanoma therapy is controversial due to the unsuccessful outcomes and a still rather unclarified mechanism of action. It seemed that the days of tamoxifen in malignant melanoma therapy were close to an end, but new evidence may challenge this fate. On one hand, it is now believed that metabolism is a major determinant of tamoxifen clinical outcomes in breast cancer patients, which is a variable that has yet to be tested in melanoma patients, since the tamoxifen active metabolite endoxifen demonstrated superior cytostatic activity over the parent drug in melanoma cells; on the other hand, new evidence has emerged regarding estrogen-mediated signaling in melanoma cells, including the methylation of the estrogen receptor-α gene promoter and the expression of the G protein coupled estrogen receptor. The expression of estrogen receptor-α and G protein coupled estrogen receptor, as well as the cytochrome P450 (CYP) 2D6 genotype, may be used as predictive biomarkers to select the patients that may respond to antiestrogens based on specific traits of their tumors. This review focused on these new evidences and how they may contribute to shed new light on this long-lasting controversy, as well as their possible implications for future investigations.
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Affiliation(s)
- Mariana P C Ribeiro
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
| | - Armanda E Santos
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - José B A Custódio
- Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
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17
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Shang D, Li Z, Zhu Z, Chen H, Zhao L, Wang X, Chen Y. Baicalein suppresses 17-β-estradiol-induced migration, adhesion and invasion of breast cancer cells via the G protein-coupled receptor 30 signaling pathway. Oncol Rep 2015; 33:2077-85. [PMID: 25672442 DOI: 10.3892/or.2015.3786] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 01/26/2015] [Indexed: 12/21/2022] Open
Abstract
Flavonoids are structurally similar to steroid hormones, particularly estrogens, and therefore have been studied for their potential effects on hormone-dependent cancers. Baicalein is the primary flavonoid derived from the root of Scutellaria baicalensis Georgi. In the present study, we investigated the effects of baicalein on 17β-estradiol (E2)-induced migration, adhesion and invasion of MCF-7 and SK-BR-3 breast cancer cells. The results demonstrated that baicalein suppressed E2-stimulated wound-healing migration and cell‑Matrigel adhesion, and ameliorated E2-promoted invasion across a Matrigel-coated Transwell membrane. Furthermore, baicalein interfered with E2-induced novel G protein-coupled estrogen receptor (GPR30)-related signaling, including a decrease in tyrosine phosphorylation of epidermal growth factor receptor (EGFR) as well as phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine kinase Akt, without affecting GPR30 expression. The results also showed that baicalein suppressed the expression of GPR30 target genes, cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF) induced by E2. Furthermore, baicalein prevented GPR30-related signaling activation and upregulation of CYR61 and CTGF mRNA levels induced by G1, a specific GPR 30 agonist. The results suggest that baicalein inhibits E2-induced migration, adhesion and invasion through interfering with GPR30 signaling pathway activation, which indicates that it may act as a therapeutic candidate for the treatment of GPR30-positive breast cancer metastasis.
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Affiliation(s)
- Dandan Shang
- Department of Physiology/Cancer Research Group, Guiyang Medical University School of Basic Medicine, Guiyang, Guizhou 550004, P.R. China
| | - Zheng Li
- Department of Physiology/Cancer Research Group, Guiyang Medical University School of Basic Medicine, Guiyang, Guizhou 550004, P.R. China
| | - Zhuxia Zhu
- Department of Physiology/Cancer Research Group, Guiyang Medical University School of Basic Medicine, Guiyang, Guizhou 550004, P.R. China
| | - Huamei Chen
- Department of Physiology/Cancer Research Group, Guiyang Medical University School of Basic Medicine, Guiyang, Guizhou 550004, P.R. China
| | - Lujun Zhao
- Department of Pharmacology of Chinese Material Medica, Guiyang Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Xudong Wang
- Department of Physiology/Cancer Research Group, Guiyang Medical University School of Basic Medicine, Guiyang, Guizhou 550004, P.R. China
| | - Yan Chen
- Department of Pharmacology of Chinese Material Medica, Guiyang Medical University, Guiyang, Guizhou 550004, P.R. China
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18
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De Marco P, Cirillo F, Vivacqua A, Malaguarnera R, Belfiore A, Maggiolini M. Novel Aspects Concerning the Functional Cross-Talk between the Insulin/IGF-I System and Estrogen Signaling in Cancer Cells. Front Endocrinol (Lausanne) 2015; 6:30. [PMID: 25798130 PMCID: PMC4351617 DOI: 10.3389/fendo.2015.00030] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 02/19/2015] [Indexed: 12/13/2022] Open
Abstract
The insulin/IGF system plays an important role in cancer progression. Accordingly, elevated levels of circulating insulin have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes. Numerous studies have documented that estrogens cooperate with the insulin/IGF system in multiple pathophysiological conditions. The biological responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as transcription factors; however, several studies have recently demonstrated that a member of the G protein-coupled receptors, named GPR30/G-protein estrogen receptor (GPER), is also involved in the estrogen signaling in normal and malignant cells as well as in cancer-associated fibroblasts (CAFs). In this regard, novel mechanisms linking the action of estrogens through GPER with the insulin/IGF system have been recently demonstrated. This review recapitulates the relevant aspects of this functional cross-talk between the insulin/IGF and the estrogenic GPER transduction pathways, which occurs in various cell types and may account for cancer progression.
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Affiliation(s)
- Paola De Marco
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Adele Vivacqua
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Roberta Malaguarnera
- Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonino Belfiore, Università degli Studi Magna Graecia di Catanzaro, Viale Europa, Loc. Germaneto, Catanzaro 88100, Italy e-mail: ; Marcello Maggiolini, Università della Calabria, via P. Bucci, Rende 87036, Italy e-mail:
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
- *Correspondence: Antonino Belfiore, Università degli Studi Magna Graecia di Catanzaro, Viale Europa, Loc. Germaneto, Catanzaro 88100, Italy e-mail: ; Marcello Maggiolini, Università della Calabria, via P. Bucci, Rende 87036, Italy e-mail:
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19
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Zhang K, Shen Z, Liang X, Liu T, Wang T, Jiang Y. Down-regulation of GPR137 expression inhibits proliferation of colon cancer cells. Acta Biochim Biophys Sin (Shanghai) 2014; 46:935-41. [PMID: 25301753 DOI: 10.1093/abbs/gmu086] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
G protein-coupled receptors (GPRs) are highly related to oncogenesis and cancer metastasis. G protein-coupled receptor 137 (GPR137) was initially reported as a novel orphan GPR about 10 years ago. Some orphan GPRs have been implicated in human cancers. The aim of this study is to investigate the role of GPR137 in human colon cancer. Expression levels of GRP137 were analyzed in different colon cancer cell lines by quantitative polymerase chain reaction and western blot analysis. Lentivirus-mediated short hairpin RNA was specifically designed to knock down GPR137 expression in colon cancer cells. Cell viability was measured by methylthiazoletetrazolium and colony formation assays. In addition, cell cycle characteristic was investigated by flow cytometry. GRP137 expression was observed in all seven colon cancer cell lines at different levels. The mRNA and protein levels of GPR137 were down-regulated in both HCT116 and RKO cells after lentivirus infection. Lentivirus-mediated silencing of GPR137 reduced the proliferation rate and colonies numbers. Knockdown of GPR137 in both cell lines led to cell cycle arrest in the G0/G1 phase. These results indicated that GPR137 plays an important role in colon cancer cell proliferation. A better understanding of GPR137's effects on signal transduction pathways in colon cancer cells may provide insights into the novel gene therapy of colon cancer.
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Affiliation(s)
- Kai Zhang
- Department of Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130031, China
| | - Zhen Shen
- Department of Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130031, China
| | - Xianjun Liang
- Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
| | - Tongjun Liu
- Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
| | - Tiejun Wang
- Department of General Surgery, Taizhou Central Hospital, Taizhou 318000, China
| | - Yang Jiang
- Department of Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130031, China
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20
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Wegner MS, Wanger RA, Oertel S, Brachtendorf S, Hartmann D, Schiffmann S, Marschalek R, Schreiber Y, Ferreirós N, Geisslinger G, Grösch S. Ceramide synthases CerS4 and CerS5 are upregulated by 17β-estradiol and GPER1 via AP-1 in human breast cancer cells. Biochem Pharmacol 2014; 92:577-89. [PMID: 25451689 DOI: 10.1016/j.bcp.2014.10.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 10/09/2014] [Accepted: 10/16/2014] [Indexed: 12/23/2022]
Abstract
Ceramide synthases (CerS) are important enzymes of the sphingolipid pathway, responsible for the production of ceramides with distinct chain lengths. In human breast cancer tissue, we detected a significant increase in CerS4 and CerS6 mRNA in estrogen receptor positive (ER+) cancer tissue. To clarify the molecular mechanism of this upregulation, we cloned CerS2, -4, -5 and CerS6 promoter and 3'-UTR fragments into luciferase reporter gene plasmids and determined luciferase activity in MCF-7 (ERα/β) and MDA-MB-231 (ERβ) cells after 17β-estradiol treatment. Only the activities of CerS4 and CerS5 promoter Luc constructs, as well as CerS2- and CerS5-3'-UTR Luc constructs increased after estradiol treatment in MCF-7 cells, and this could be inhibited by the anti-estrogen fulvestrant. Co-transfection with the G protein-coupled estrogen receptor 1 (GPER1) also enhanced CerS2, CerS4 and CerS6 promoter activity whereas CerS5 promoter activity was inhibited in both cell lines. Promoter deletion and mutation constructs from CerS4 and CerS5 promoters revealed that estradiol and GPER1 mediate their effects on both promoters by activating AP-1, most likely through dimerization of c-Jun and c-Fos. At least we could show, that cell proliferation induced by estradiol could be blocked by co-treatment with Fumonisin B1, indicating that upregulation of CerS in breast cancer cells by estrogen is important for cell proliferation and possibly tumor development. In conclusion, our data highlight transcriptional and posttranscriptional mechanisms regulating CerS expression in human cells which provide the basis for further studies investigating the regulation of CerS expression and ceramide synthesis after diverse stimuli in physiological and pathophysiological processess.
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Affiliation(s)
- Marthe-Susanna Wegner
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Ruth Anna Wanger
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Stephanie Oertel
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Sebastian Brachtendorf
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Daniela Hartmann
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Susanne Schiffmann
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - Rolf Marschalek
- Institute for Pharmaceutical Biology, Biozentrum, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany
| | - Yannick Schreiber
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Nerea Ferreirós
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Gerd Geisslinger
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
| | - Sabine Grösch
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
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21
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Nayak TK, Ramesh C, Hathaway HJ, Norenberg JP, Arterburn JB, Prossnitz ER. GPER-targeted, 99mTc-labeled, nonsteroidal ligands demonstrate selective tumor imaging and in vivo estrogen binding. Mol Cancer Res 2014; 12:1635-43. [PMID: 25030373 DOI: 10.1158/1541-7786.mcr-14-0289] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
UNLABELLED Our understanding of estrogen (17β-estradiol, E2) receptor biology has evolved in recent years with the discovery and characterization of a 7-transmembrane-spanning G protein-coupled estrogen receptor (GPER/GPR30) and the development of GPER-selective functional chemical probes. GPER is highly expressed in certain breast, endometrial, and ovarian cancers, establishing the importance of noninvasive methods to evaluate GPER expression in vivo. Here, we developed (99m)Tc-labeled GPER ligands to demonstrate the in vivo status of GPER as an estrogen receptor (ER) and for GPER visualization in whole animals. A series of (99m)Tc(I)-labeled nonsteroidal tetrahydro-3H-cyclopenta[c]quinolone derivatives was synthesized utilizing pyridin-2-yl hydrazine and picolylamine chelates. Radioligand receptor binding studies revealed binding affinities in the 10 to 30 nmol/L range. Cell signaling assays previously demonstrated that derivatives retaining a ketone functionality displayed agonist properties, whereas those lacking such a hydrogen bond acceptor were antagonists. In vivo biodistribution and imaging studies performed on mice bearing human endometrial and breast cancer cell xenografts yielded significant tumor uptake (0.4-1.1%ID/g). Blocking studies revealed specific uptake in multiple organs (adrenals, uterus, and mammary tissue), as well as tumor uptake with similar levels of competition by E2 and G-1, a GPER-selective agonist. In conclusion, we synthesized and evaluated a series of first-generation (99m)Tc-labeled GPER-specific radioligands, demonstrating GPER as an estrogen-binding receptor for the first time in vivo using competitive binding principles, and establishing the utility of such ligands as tumor imaging agents. These results warrant further investigation into the role of GPER in estrogen-mediated carcinogenesis and as a target for diagnostic/therapeutic/image-guided drug delivery. IMPLICATIONS These studies provide a molecular basis to evaluate GPER expression and function as an ER through in vivo imaging.
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Affiliation(s)
- Tapan K Nayak
- Department of Cell Biology and Physiology, School of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico. College of Pharmacy, University of New Mexico Health Science Center, Albuquerque, New Mexico
| | - Chinnasamy Ramesh
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico
| | - Helen J Hathaway
- Department of Cell Biology and Physiology, School of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico. University of New Mexico Cancer Center, University of New Mexico Health Science Center, Albuquerque, New Mexico
| | - Jeffrey P Norenberg
- College of Pharmacy, University of New Mexico Health Science Center, Albuquerque, New Mexico. University of New Mexico Cancer Center, University of New Mexico Health Science Center, Albuquerque, New Mexico
| | - Jeffrey B Arterburn
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico. University of New Mexico Cancer Center, University of New Mexico Health Science Center, Albuquerque, New Mexico
| | - Eric R Prossnitz
- Department of Cell Biology and Physiology, School of Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico. University of New Mexico Cancer Center, University of New Mexico Health Science Center, Albuquerque, New Mexico.
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Prossnitz ER, Barton M. Estrogen biology: new insights into GPER function and clinical opportunities. Mol Cell Endocrinol 2014; 389:71-83. [PMID: 24530924 PMCID: PMC4040308 DOI: 10.1016/j.mce.2014.02.002] [Citation(s) in RCA: 289] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 02/04/2014] [Indexed: 12/16/2022]
Abstract
Estrogens play an important role in the regulation of normal physiology, aging and many disease states. Although the nuclear estrogen receptors have classically been described to function as ligand-activated transcription factors mediating genomic effects in hormonally regulated tissues, more recent studies reveal that estrogens also mediate rapid signaling events traditionally associated with G protein-coupled receptors. The G protein-coupled estrogen receptor GPER (formerly GPR30) has now become recognized as a major mediator of estrogen's rapid cellular effects throughout the body. With the discovery of selective synthetic ligands for GPER, both agonists and antagonists, as well as the use of GPER knockout mice, significant advances have been made in our understanding of GPER function at the cellular, tissue and organismal levels. In many instances, the protective/beneficial effects of estrogen are mimicked by selective GPER agonism and are absent or reduced in GPER knockout mice, suggesting an essential or at least parallel role for GPER in the actions of estrogen. In this review, we will discuss recent advances and our current understanding of the role of GPER and the activity of clinically used drugs, such as SERMs and SERDs, in physiology and disease. We will also highlight novel opportunities for clinical development towards GPER-targeted therapeutics, for molecular imaging, as well as for theranostic approaches and personalized medicine.
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Affiliation(s)
- Eric R Prossnitz
- Department of Cell Biology and Physiology, UNM Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87120, USA.
| | - Matthias Barton
- Molecular Internal Medicine, University of Zurich, Switzerland.
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Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell-matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis. Toxicol Appl Pharmacol 2014; 275:176-81. [PMID: 24440569 DOI: 10.1016/j.taap.2014.01.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 01/08/2014] [Accepted: 01/09/2014] [Indexed: 12/14/2022]
Abstract
Fulvestrant (ICI 182 780, ICI) has been used in treating patients with hormone-sensitive breast cancer, yet initial or acquired resistance to endocrine therapies frequently arises and, in particular, cancer recurs as metastasis. We demonstrate here that both 17-beta-estradiol (E2) and ICI enhance cell adhesion to matrigel in MCF-7 breast cancer cells, with increased autolysis of calpain 1 (large subunit) and proteolysis of focal adhesion kinase (FAK), indicating calpain activation. Additionally, either E2 or ICI induced down-regulation of estrogen receptor α without affecting G protein coupled estrogen receptor 30 (GPR30) expression. Interestingly, GPR30 agonist G1 triggered calpain 1 autolysis but not calpain 2, whereas ER agonist diethylstilbestrol caused no apparent calpain autolysis. Furthermore, the actions of E2 and ICI on calpain and cell adhesion were tremendously suppressed by G15, or knockdown of GPR30. E2 and ICI also induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 phosphorylation by U0126 profoundly impeded calpain activation triggered by estrogenic and antiestrogenic stimulations indicating implication of ERK1/2 in the GPR30-mediated action. Lastly, the E2- or ICI-induced cell adhesion was dramatically impaired by calpain-specific inhibitors, ALLN or calpeptin, suggesting requirement of calpain in the GPR30-associated action. These data show that enhanced cell adhesion by E2 and ICI occurs via a novel GPR30-ERK1/2-calpain pathway. Our results indicate that targeting the GPR30 signaling may be a potential strategy to reduce metastasis and improve the efficacy of antiestrogens in treatment of advanced breast cancer.
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Lappano R, Pisano A, Maggiolini M. GPER Function in Breast Cancer: An Overview. Front Endocrinol (Lausanne) 2014; 5:66. [PMID: 24834064 PMCID: PMC4018520 DOI: 10.3389/fendo.2014.00066] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 04/17/2014] [Indexed: 12/31/2022] Open
Abstract
The G-protein-coupled estrogen receptor-1 (GPER, formerly known as GPR30) has attracted increasing interest, considering its ability to mediate estrogenic signaling in different cell types, including the hormone-sensitive tumors like breast cancer. As observed for other GPCR-mediated responses, the activation of the epidermal growth factor receptor is a fundamental integration point in the biological action triggered by GPER. A wide number of natural and synthetic compounds, including estrogens and anti-estrogens, elicit stimulatory effects in breast cancer through GPER up-regulation and activation, suggesting that GPER function is associated with breast tumor progression and tamoxifen resistance. GPER has also been proposed as a candidate biomarker in triple-negative breast cancer, opening a novel scenario for a more comprehensive assessment of breast tumor patients.
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Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
- *Correspondence: Rosamaria Lappano, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, Rende 87036, Italy e-mail:
| | - Assunta Pisano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
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Chimento A, Casaburi I, Rosano C, Avena P, De Luca A, Campana C, Martire E, Santolla MF, Maggiolini M, Pezzi V, Sirianni R. Oleuropein and hydroxytyrosol activate GPER/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells. Mol Nutr Food Res 2013; 58:478-89. [PMID: 24019118 DOI: 10.1002/mnfr.201300323] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 07/03/2013] [Accepted: 07/30/2013] [Indexed: 12/23/2022]
Abstract
SCOPE We have previously demonstrated that oleuropein (OL) and hydroxytyrosol (HT) reduce 17β-estradiol-mediated proliferation in MCF-7 breast cancer (BC) cells without affecting the classical genomic action of estrogen receptor (ER), but activating instead the ERK1/2 pathway. Here, we hypothesized that this inhibition could be mediated by a G-protein-coupled receptor named GPER/GPR30. Using the ER-negative and GPER-positive SKBR3 BC cells as experimental model, we investigated the effects of OL and HT on GPER-mediated activation of downstream pathways. METHODS AND RESULTS Docking simulations and ligand-binding studies evidenced that OL and HT are able to bind GPER. MTT cell proliferation assays revealed that both phenols reduced SKBR3 cell growth; this effect was abolished silencing GPER. Focusing on OL and HT GPER-mediated pathways, using Western blot analysis we showed a sustained ERK1/2 activation triggering an intrinsic apoptotic pathway. CONCLUSION Showing that OL and HT work as GPER inverse agonists in ER-negative and GPER-positive SKBR3 BC cells, we provide novel insights into the potential of these two molecules as tools in the therapy of this subtype of BC.
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Affiliation(s)
- Adele Chimento
- Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, Cosenza, Italy
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