|
1
|
Xu M, Xu B. Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics. Mol Cancer 2025; 24:138. [PMID: 40335986 PMCID: PMC12057185 DOI: 10.1186/s12943-025-02309-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/18/2025] [Indexed: 05/09/2025] Open
Abstract
Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.
Collapse
Affiliation(s)
- Mengke Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Intelligent Oncology Innovation Center Designated by the Ministry of Education, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Intelligent Oncology Innovation Center Designated by the Ministry of Education, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China.
| |
Collapse
|
|
2
|
Li T, Thoen ZE, Applebaum JM, Khalil RA. Menopause-related changes in vascular signaling by sex hormones. J Pharmacol Exp Ther 2025; 392:103526. [PMID: 40184819 DOI: 10.1016/j.jpet.2025.103526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 02/24/2025] [Indexed: 04/07/2025] Open
Abstract
Cardiovascular disease (CVD), such as hypertension and coronary artery disease, involves pathological changes in vascular signaling, function, and structure. Vascular signaling is regulated by multiple intrinsic and extrinsic factors that influence endothelial cells, vascular smooth muscle, and extracellular matrix. Vascular function is also influenced by environmental factors including diet, exercise, and stress, as well as genetic background, sex differences, and age. CVD is more common in adult men and postmenopausal women than in premenopausal women. Specifically, women during menopausal transition, with declining ovarian function and production of estrogen (E2) and progesterone, show marked increase in the incidence of CVD and associated vascular dysfunction. Mechanistic research suggests that E2 and E2 receptor signaling have beneficial effects on vascular function including vasodilation, decreased blood pressure, and cardiovascular protection. Also, the tangible benefits of E2 supplementation in improving menopausal symptoms have prompted clinical trials of menopausal hormone therapy (MHT) in CVD, but the results have been inconsistent. The inadequate benefits of MHT in CVD could be attributed to the E2 type, dose, formulation, route, timing, and duration as well as menopausal changes in E2/E2 receptor vascular signaling. Other factors that could affect the responsiveness to MHT are the integrated hormonal milieu including gonadotropins, progesterone, and testosterone, vascular health status, preexisting cardiovascular conditions, and menopause-related dysfunction in the renal, gastrointestinal, endocrine, immune, and nervous systems. Further analysis of these factors should enhance our understanding of menopause-related changes in vascular signaling by sex hormones and provide better guidance for management of CVD in postmenopausal women. SIGNIFICANCE STATEMENT: Cardiovascular disease is more common in adult men and postmenopausal women than premenopausal women. Earlier observations of vascular benefits of menopausal hormone therapy did not materialize in randomized clinical trials. Further examination of the cardiovascular effects of sex hormones in different formulations and regimens, and the menopausal changes in vascular signaling would help to adjust the menopausal hormone therapy protocols in order to enhance their effectiveness in reducing the risk and the management of cardiovascular disease in postmenopausal women.
Collapse
Affiliation(s)
- Tao Li
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Zachary E Thoen
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Jessica M Applebaum
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Raouf A Khalil
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
| |
Collapse
|
|
3
|
Catalán-Salas V, Sagredo P, Melgarejo W, Donoso MV, Cárdenas JC, Zakarian A, Valdés D, Acuña-Castillo C, Huidobro-Toro JP. 17-β-estradiol and phytoestrogens elicit NO production and vasodilatation through PI3K, PKA and EGF receptors pathways, evidencing functional selectivity. Eur J Pharmacol 2024; 975:176636. [PMID: 38729417 DOI: 10.1016/j.ejphar.2024.176636] [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: 12/28/2023] [Revised: 04/24/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024]
Abstract
Endothelial cells express multiple receptors mediating estrogen responses; including the G protein-coupled estrogen receptor (GPER). Past studies on nitric oxide (NO) production elicited by estrogens raised the question whether 17-β-estradiol (E2) and natural phytoestrogens activate equivalent mechanisms. We hypothesized that E2 and phytoestrogens elicit NO production via coupling to distinct intracellular pathways signalling. To this aim, perfusion of E2 and phytoestrogens to the precontracted rat mesentery bed examined vasorelaxation, while fluorescence microscopy on primary endothelial cells cultures quantified single cell NO production determined following 4-amino-5-methylamino-2',7'-difluoroescein diacetate (DAF) incubation. Daidzein (DAI) and genistein (GEN) induced rapid vasodilatation associated to NO production. Multiple estrogen receptor activity was inferred based on the reduction of DAF-NO signals; G-36 (GPER antagonist) reduced 75 % of all estrogen responses, while fulvestrant (selective nuclear receptor antagonist) reduced significantly more the phytoestrogens responses than E2. The joint application of both antagonists abolished the E2 response but not the phytoestrogen-induced DAF-NO signals. Wortmannin or LY-294002 (PI3K inhibitors), reduced by 90% the E2-evoked signal while altering significantly less the DAI-induced response. In contrast, H-89 (PKA inhibitor), elicited a 23% reduction of the E2-induced signal while blocking 80% of the DAI-induced response. Desmethylxestospongin-B (IP3 receptor antagonist), decreased to equal extent the E2 or the DAI-induced signal. Epidermal growth factor (EGF) induced NO production, cell treatment with AG-1478, an EGF receptor kinase inhibitor reduced 90% DAI-induced response while only 53% the E2-induced signals; highlighting GPER induced EGF receptor trans-modulation. Receptor functional selectivity may explain distinct signalling pathways mediated by E2 and phytoestrogens.
Collapse
Affiliation(s)
- Vicente Catalán-Salas
- Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, 9170022, Chile
| | - Pablo Sagredo
- Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, 9170022, Chile
| | - Williams Melgarejo
- Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, 9170022, Chile
| | - M Verónica Donoso
- Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, 9170022, Chile
| | - J Cesar Cárdenas
- Centro de Biología Integrativa, Facultad de Ciencias, Universidad Mayor, Santiago, 8580745, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, 8580745, Chile; Buck Institute for Research on Aging, Novato, CA, 94945, USA; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA
| | - Armen Zakarian
- Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA
| | - Daniel Valdés
- Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, 9170022, Chile
| | - Claudio Acuña-Castillo
- Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, 9170022, Chile
| | - J Pablo Huidobro-Toro
- Laboratorio de Farmacología, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, 9170022, Chile; Unidad de Nanoseguridad, Centro de Nanociencia y Nanotecnología, CEDNNA, Santiago, Chile.
| |
Collapse
|
|
4
|
Hancock GR, Gertz J, Jeselsohn R, Fanning SW. Estrogen Receptor Alpha Mutations, Truncations, Heterodimers, and Therapies. Endocrinology 2024; 165:bqae051. [PMID: 38643482 PMCID: PMC11075793 DOI: 10.1210/endocr/bqae051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 04/02/2024] [Accepted: 04/17/2024] [Indexed: 04/23/2024]
Abstract
Annual breast cancer (BCa) deaths have declined since its apex in 1989 concomitant with widespread adoption of hormone therapies that target estrogen receptor alpha (ERα), the prominent nuclear receptor expressed in ∼80% of BCa. However, up to ∼50% of patients who are ER+ with high-risk disease experience post endocrine therapy relapse and metastasis to distant organs. The vast majority of BCa mortality occurs in this setting, highlighting the inadequacy of current therapies. Genomic abnormalities to ESR1, the gene encoding ERα, emerge under prolonged selective pressure to enable endocrine therapy resistance. These genetic lesions include focal gene amplifications, hotspot missense mutations in the ligand binding domain, truncations, fusions, and complex interactions with other nuclear receptors. Tumor cells utilize aberrant ERα activity to proliferate, spread, and evade therapy in BCa as well as other cancers. Cutting edge studies on ERα structural and transcriptional relationships are being harnessed to produce new therapies that have shown benefits in patients with ESR1 hotspot mutations. In this review we discuss the history of ERα, current research unlocking unknown aspects of ERα signaling including the structural basis for receptor antagonism, and future directions of ESR1 investigation. In addition, we discuss the development of endocrine therapies from their inception to present day and survey new avenues of drug development to improve pharmaceutical profiles, targeting, and efficacy.
Collapse
Affiliation(s)
- Govinda R Hancock
- Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60513, USA
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Center, University of Utah, Salt Lake City, UT 84112, USA
| | - Rinath Jeselsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Sean W Fanning
- Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60513, USA
| |
Collapse
|
|
5
|
Tanaka Y, Nagoshi T, Takahashi H, Oi Y, Yasutake R, Yoshii A, Kimura H, Kashiwagi Y, Tanaka TD, Shimoda M, Yoshimura M. URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease. iScience 2023; 26:107730. [PMID: 37694143 PMCID: PMC10483053 DOI: 10.1016/j.isci.2023.107730] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 05/17/2023] [Accepted: 08/23/2023] [Indexed: 09/12/2023] Open
Abstract
We recently reported that the selective inhibition of urate transporter-1 (URAT1), which is primarily expressed in the kidneys, ameliorates insulin resistance by attenuating hepatic steatosis and improving brown adipose tissue function in diet-induced obesity. In this study, we evaluated the effects of dotinurad, a URAT1-selective inhibitor, on the hearts of high-fat diet (HFD)-fed obese mice for 16-20 weeks and on neonatal rat cardiomyocytes (NRCMs) exposed to palmitic acid. Outside the kidneys, URAT1 was also expressed in cardiomyocytes and indeed worked as a uric acid transporter. Dotinurad substantially attenuated HFD-induced cardiac fibrosis, inflammatory responses, and cardiac dysfunction. Intriguingly, among various factors related to the pathophysiology of diet-induced obesity, palmitic acid significantly increased URAT1 expression in NRCMs and subsequently induced apoptosis, oxidative stress, and inflammatory responses via MAPK pathway, all of which were reduced by dotinurad. These results indicate that URAT1 is a potential therapeutic target for metabolic heart disease.
Collapse
Affiliation(s)
- Yoshiro Tanaka
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Tomohisa Nagoshi
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Hirotake Takahashi
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Yuhei Oi
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Rei Yasutake
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Akira Yoshii
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Haruka Kimura
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Yusuke Kashiwagi
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Toshikazu D. Tanaka
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Masayuki Shimoda
- Department of Pathology, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Michihiro Yoshimura
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
| |
Collapse
|
|
6
|
Zhu Z, Jiang L, Ding X. Advancing Breast Cancer Heterogeneity Analysis: Insights from Genomics, Transcriptomics and Proteomics at Bulk and Single-Cell Levels. Cancers (Basel) 2023; 15:4164. [PMID: 37627192 PMCID: PMC10452610 DOI: 10.3390/cancers15164164] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/23/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer continues to pose a significant healthcare challenge worldwide for its inherent molecular heterogeneity. This review offers an in-depth assessment of the molecular profiling undertaken to understand this heterogeneity, focusing on multi-omics strategies applied both in traditional bulk and single-cell levels. Genomic investigations have profoundly informed our comprehension of breast cancer, enabling its categorization into six intrinsic molecular subtypes. Beyond genomics, transcriptomics has rendered deeper insights into the gene expression landscape of breast cancer cells. It has also facilitated the formulation of more precise predictive and prognostic models, thereby enriching the field of personalized medicine in breast cancer. The comparison between traditional and single-cell transcriptomics has identified unique gene expression patterns and facilitated the understanding of cell-to-cell variability. Proteomics provides further insights into breast cancer subtypes by illuminating intricate protein expression patterns and their post-translational modifications. The adoption of single-cell proteomics has been instrumental in this regard, revealing the complex dynamics of protein regulation and interaction. Despite these advancements, this review underscores the need for a holistic integration of multiple 'omics' strategies to fully decipher breast cancer heterogeneity. Such integration not only ensures a comprehensive understanding of breast cancer's molecular complexities, but also promotes the development of personalized treatment strategies.
Collapse
Affiliation(s)
- Zijian Zhu
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China;
| | - Lai Jiang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200025, China;
| | - Xianting Ding
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China;
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200025, China;
| |
Collapse
|
|
7
|
Tokiwa H, Ueda K, Takimoto E. The emerging role of estrogen's non-nuclear signaling in the cardiovascular disease. Front Cardiovasc Med 2023; 10:1127340. [PMID: 37123472 PMCID: PMC10130590 DOI: 10.3389/fcvm.2023.1127340] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
Sexual dimorphism exists in the epidemiology of cardiovascular disease (CVD), which indicates the involvement of sexual hormones in the pathophysiology of CVD. In particular, ample evidence has demonstrated estrogen's protective effect on the cardiovascular system. While estrogen receptors, bound to estrogen, act as a transcription factor which regulates gene expressions by binding to the specific DNA sequence, a subpopulation of estrogen receptors localized at the plasma membrane induces activation of intracellular signaling, called "non-nuclear signaling" or "membrane-initiated steroid signaling of estrogen". Although the precise molecular mechanism of non-nuclear signaling as well as its physiological impact was unclear for a long time, recent development of genetically modified animal models and pathway-selective estrogen receptor stimulant bring new insights into this pathway. We review the published experimental studies on non-nuclear signaling of estrogen, and summarize its role in cardiovascular system, especially focusing on: (1) the molecular mechanism of non-nuclear signaling; (2) the design of genetically modified animals and pathway-selective stimulant of estrogen receptor.
Collapse
Affiliation(s)
- Hiroyuki Tokiwa
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazutaka Ueda
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Eiki Takimoto
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| |
Collapse
|
|
8
|
Clusan L, Ferrière F, Flouriot G, Pakdel F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int J Mol Sci 2023; 24:ijms24076834. [PMID: 37047814 PMCID: PMC10095386 DOI: 10.3390/ijms24076834] [Citation(s) in RCA: 118] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/31/2023] [Accepted: 04/01/2023] [Indexed: 04/08/2023] Open
Abstract
Breast cancer is the most common cancer and the deadliest among women worldwide. Estrogen signaling is closely associated with hormone-dependent breast cancer (estrogen and progesterone receptor positive), which accounts for two-thirds of tumors. Hormone therapy using antiestrogens is the gold standard, but resistance to these treatments invariably occurs through various biological mechanisms, such as changes in estrogen receptor activity, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle dysregulations. All these factors have led to the development of new therapies, such as selective estrogen receptor degraders (SERDs), or combination therapies with cyclin-dependent kinases (CDK) 4/6 or PI3K inhibitors. Therefore, understanding the estrogen pathway is essential for the treatment and new drug development of hormone-dependent cancers. This mini-review summarizes current literature on the signalization, mechanisms of action and clinical implications of estrogen receptors in breast cancer.
Collapse
Affiliation(s)
- Léa Clusan
- Université de Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, F-35000 Rennes, France
| | - François Ferrière
- Université de Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, F-35000 Rennes, France
| | - Gilles Flouriot
- Université de Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, F-35000 Rennes, France
| | - Farzad Pakdel
- Université de Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, F-35000 Rennes, France
| |
Collapse
|
|
9
|
Shields CA, Wang X, Cornelius DC. Sex differences in cardiovascular response to sepsis. Am J Physiol Cell Physiol 2023; 324:C458-C466. [PMID: 36571442 PMCID: PMC9902216 DOI: 10.1152/ajpcell.00134.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 12/20/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022]
Abstract
Recently, there has been increased recognition of the importance of sex as a biological factor affecting disease and health. Many preclinical studies have suggested that males may experience a less favorable outcome in response to sepsis than females. The underlying mechanisms for these differences are still largely unknown but are thought to be related to the beneficial effects of estrogen. Furthermore, the immunosuppressive role of testosterone is also thought to contribute to the sex-dependent differences that are present in clinical sepsis. There are still significant knowledge gaps in this field. This mini-review will provide a brief overview of sex-dependent variables in relation to sepsis and the cardiovascular system. Preclinical animal models for sepsis research will also be discussed. The intent of this mini-review is to inspire interest for future considerations of sex-related variables in sepsis that should be addressed to increase our understanding of the underlying mechanisms in sepsis-induced cardiovascular dysfunction for the identification of therapeutic targets and improved sepsis management and treatment.
Collapse
Affiliation(s)
- Corbin A Shields
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Xi Wang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Denise C Cornelius
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| |
Collapse
|
|
10
|
Grinshpun A, Chen V, Sandusky ZM, Fanning SW, Jeselsohn R. ESR1 activating mutations: From structure to clinical application. Biochim Biophys Acta Rev Cancer 2023; 1878:188830. [PMID: 36336145 DOI: 10.1016/j.bbcan.2022.188830] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022]
Abstract
Estrogen receptor-positive breast cancer is the most common type of both early and advanced breast cancer. Estrogen receptor alpha (ER) is a nuclear hormone receptor and a key driver of tumorigenesis and tumor progression in these breast cancers. As such, it is a key treatment target and a biomarker predictive of response to endocrine therapy. Activating ESR1 ligand binding domain mutations engender constitutive/ligand independent transcriptional activities and emerge following prolonged first-line hormone therapy regimens, mainly from aromatase inhibitors. The full scale of the biological and clinical significance of these mutations continue to evolve and additional studies are required to further discern the multimodal effects of these mutations on ER transcription, metastatic propensity, and the tumor microenvironment. Furthermore, recent and ongoing studies highlight the potential clinical utility of these mutations as therapeutic targets and dynamic biomarkers. Herein, we review the structure, functional consequences, and clinical implications of the activating ESR1 mutations in advanced estrogen receptor-positive breast cancer.
Collapse
Affiliation(s)
- Albert Grinshpun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America; Breast Oncology Center, Dana-Farber Cancer Center, Boston, MA, United States of America
| | - Vincent Chen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America; Breast Oncology Center, Dana-Farber Cancer Center, Boston, MA, United States of America
| | - Zachary M Sandusky
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America; Center for Functional Cancer Epigenetics, Dana Farber-Cancer Institute, Boston, MA, United States of America
| | - Sean W Fanning
- Department of Cancer Biology, Loyola University, Chicago, IL, United States of America
| | - Rinath Jeselsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America; Breast Oncology Center, Dana-Farber Cancer Center, Boston, MA, United States of America; Center for Functional Cancer Epigenetics, Dana Farber-Cancer Institute, Boston, MA, United States of America.
| |
Collapse
|
|
11
|
Khan MZI, Uzair M, Nazli A, Chen JZ. An overview on Estrogen receptors signaling and its ligands in breast cancer. Eur J Med Chem 2022; 241:114658. [PMID: 35964426 DOI: 10.1016/j.ejmech.2022.114658] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 02/07/2023]
Abstract
Estrogen governs the regulations of various pathological and physiological actions throughout the body in both males and females. Generally, 17β-estradiol an endogenous estrogen is responsible for different health problems in pre and postmenopausal women. The major activities of endogenous estrogen are executed by nuclear estrogen receptors (ERs) ERα and ERβ while non-genomic cytoplasmic pathways also govern cell growth and apoptosis. Estrogen accomplished a fundamental role in the formation and progression of breast cancer. In this review, we have hyphenated different studies regarding ERs and a thorough and detailed study of estrogen receptors is presented. This review highlights different aspects of estrogens ranging from receptor types, their isoforms, structures, signaling pathways of ERα, ERβ and GPER along with their crystal structures, pathological roles of ER, ER ligands, and therapeutic strategies to overcome the resistance.
Collapse
Affiliation(s)
| | - Muhammad Uzair
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China
| | - Adila Nazli
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Jian-Zhong Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
| |
Collapse
|
|
12
|
Macrophages Upregulate Estrogen Receptor Expression in the Model of Obesity-Associated Breast Carcinoma. Cells 2022; 11:cells11182844. [PMID: 36139419 PMCID: PMC9496942 DOI: 10.3390/cells11182844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 11/17/2022] Open
Abstract
Breast cancer (BC) and obesity are two heterogeneous conditions with a tremendous impact on health. BC is the most commonly diagnosed neoplasm and the leading cause of cancer-related mortality among women, and the prevalence of obesity in women worldwide reaches pandemic proportions. Obesity is a significant risk factor for both incidence and worse prognosis in estrogen receptor positive (ER+) BC. Yet, the mechanisms underlying the association between excess adiposity and increased risk/therapy resistance/poorer outcome of ER+, but not ER−negative (ER−), BC are not fully understood. Tumor-promoting action of obesity, predominantly in ER + BC patients, is often attributed to the augmented production of estrogen in ‘obese’ adipose tissue. However, in addition to the estrogen production, expression levels of ER represent a key determinant in hormone-driven breast tumorigenesis and therapy response. Here, utilizing in vitro and in vivo models of BC, we show that macrophages, whose adverse activation by obesogenic substances is fueled by heparanase (extracellular matrix-degrading enzyme), are capable of upregulating ER expression in tumor cells, in the setting of obesity-associated BC. These findings underscore a previously unknown mechanism through which interplay between cellular/extracellular elements of obesity-associated BC microenvironment influences estrogen sensitivity—a critical component in hormone-related cancer progression and resistance to therapy.
Collapse
|
|
13
|
Chromatin modifiers – Coordinators of estrogen action. Biomed Pharmacother 2022; 153:113548. [DOI: 10.1016/j.biopha.2022.113548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 08/03/2022] [Accepted: 08/11/2022] [Indexed: 11/20/2022] Open
|
|
14
|
Davezac M, Buscato M, Zahreddine R, Lacolley P, Henrion D, Lenfant F, Arnal JF, Fontaine C. Estrogen Receptor and Vascular Aging. FRONTIERS IN AGING 2022; 2:727380. [PMID: 35821994 PMCID: PMC9261451 DOI: 10.3389/fragi.2021.727380] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/10/2021] [Indexed: 12/13/2022]
Abstract
Cardiovascular diseases remain an age-related pathology in both men and women. These pathologies are 3-fold more frequent in men than in women before menopause, although this difference progressively decreases after menopause. The vasculoprotective role of estrogens are well established before menopause, but the consequences of their abrupt decline on the cardiovascular risk at menopause remain debated. In this review, we will attempt to summarize the main clinical and experimental studies reporting the protective effects of estrogens against cardiovascular diseases, with a particular focus on atherosclerosis, and the impact of aging and estrogen deprivation on their endothelial actions. The arterial actions of estrogens, but also part of that of androgens through their aromatization into estrogens, are mediated by the estrogen receptor (ER)α and ERβ. ERs belong to the nuclear receptor family and act by transcriptional regulation in the nucleus, but also exert non-genomic/extranuclear actions. Beside the decline of estrogens at menopause, abnormalities in the expression and/or function of ERs in the tissues, and particularly in arteries, could contribute to the failure of classic estrogens to protect arteries during aging. Finally, we will discuss how recent insights in the mechanisms of action of ERα could contribute to optimize the hormonal treatment of the menopause.
Collapse
Affiliation(s)
- Morgane Davezac
- INSERM-UPS UMR U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
| | - Melissa Buscato
- INSERM-UPS UMR U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
| | - Rana Zahreddine
- INSERM-UPS UMR U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
| | - Patrick Lacolley
- INSERM, UMR_S 1116, DCAC Institute, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Daniel Henrion
- INSERM U1083 CNRS UMR 6015, CHU, MITOVASC Institute and CARFI Facility, Université d'Angers, Angers, France
| | - Francoise Lenfant
- INSERM-UPS UMR U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
| | - Jean-Francois Arnal
- INSERM-UPS UMR U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
| | - Coralie Fontaine
- INSERM-UPS UMR U1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
| |
Collapse
|
|
15
|
Afrin S, El Sabeh M, Miyashita-Ishiwata M, Charewycz N, Singh B, Borahay MA. Simvastatin reduces plasma membrane caveolae and caveolin-1 in uterine leiomyomas. Life Sci 2022; 304:120708. [PMID: 35705139 DOI: 10.1016/j.lfs.2022.120708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 11/18/2022]
Abstract
AIMS Uterine leiomyomas, or fibroids, are estrogen dependent benign tumor in women, however, they have limited treatment options. Simvastatin, a drug commonly used to treat high cholesterol. Recently we demonstrated that simvastatin alters estrogen signaling by reducing the expression and trafficking of the estrogen receptor-α (ER-α) in human uterine leiomyoma cells. Caveolae are invaginations of the plasma membrane where ER-α is known to localize and directly interacts with the caveolar protein caveolin-1 (CAV1). This study examines the effects of simvastatin on plasma membrane caveolae and the expression and palmitoylation of CAV1 in human leiomyomas which may influence ER-α signaling. MAIN METHODS We performed in vitro experiments using primary and immortalized human uterine leiomyoma cells. The caveolae were quantified using transmission electron microscopy. Additionally, we examined the impact of simvastatin treatment (40 mg orally per day for 12 weeks) on human leiomyoma tissue obtained from a randomized controlled trial. The CAV1 protein and mRNA levels were determined using quantitative real-time polymerase chain reactions, western blotting, and immunofluorescence analyses. KEY FINDINGS Simvastatin decreased the number of caveolae in primary leiomyoma cells and reduced CAV1 abundance in whole cells and remarkably the plasma protein fraction. It also decreased CAV1 palmitoylation, a post-translational modification associated with CAV1 activation. The effects of simvastatin on CAV1 were recapitulated in human leiomyoma tissue samples. SIGNIFICANCE Our results identify caveolae and CAV1 as novel targets of simvastatin which may contribute to the recently described effects of simvastatin on ER-α signaling and plasma membrane trafficking.
Collapse
Affiliation(s)
- Sadia Afrin
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Malak El Sabeh
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Mariko Miyashita-Ishiwata
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Natasha Charewycz
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Bhuchitra Singh
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Mostafa A Borahay
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| |
Collapse
|
|
16
|
Yonehara K, Zhou Y, Takahashi JI, Yokoyama S, Tomihara K, Noguchi M, Sakurai H. RSK-Mediated Non-canonical Activation of EphA2 by Tamoxifen. Biol Pharm Bull 2022; 45:162-168. [PMID: 35110502 DOI: 10.1248/bpb.b21-00567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The long-term administration of tamoxifen to estrogen receptor α (ERα)-positive breast cancer patients is an established treatment that reduces mortality and recurrence. However, resistance to tamoxifen and an increased risk of endometrial cancer may occur; therefore, the mechanisms by which tamoxifen causes these adverse effects warrant further study. Tamoxifen has been shown to activate mitogen-activated protein kinase (MAPK) in an ERα-independent manner; therefore, we investigated its effects on the MAPK-mediated non-canonical activation of EphA2, a critical event regulating cell migration. Tamoxifen at slightly higher concentrations induced the rapid phosphorylation of EphA2 at Ser-897 via the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK-ribosomal S6 kinases (RSK) pathway in HeLa cells. In addition, tamoxifen significantly enhanced the migration ability of ERα-negative MDA-MB-231 breast cancer cells in RSK- and EphA2-dependent manners. Phosphorylated EphA2 was internalized and re-localized to the plasma membrane, including lamellipodia, in an RSK-dependent manner. Collectively, the present results provide novel insights into the tumor-promoting activity of tamoxifen.
Collapse
Affiliation(s)
- Keisuke Yonehara
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama.,Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama
| | - Yue Zhou
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Jun-Ichiro Takahashi
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Satoru Yokoyama
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Kei Tomihara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama
| | - Makoto Noguchi
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama
| | - Hiroaki Sakurai
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
| |
Collapse
|
|
17
|
Elliot SJ, Catanuto P, Pereira-Simon S, Xia X, Pastar I, Thaller S, Head CR, Stojadinovic O, Tomic-Canic M, Glassberg MK. Catalase, a therapeutic target in the reversal of estrogen-mediated aging. Mol Ther 2022; 30:947-962. [PMID: 34174444 PMCID: PMC8821897 DOI: 10.1016/j.ymthe.2021.06.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/30/2021] [Accepted: 06/09/2021] [Indexed: 02/04/2023] Open
Abstract
Despite increasing interest in the reversal of age-related processes, there is a paucity of data regarding the effects of post-menopausal-associated estrogen loss on cellular function. We studied human adipose-derived mesenchymal stem cells (hASCs) isolated from women younger than 45 years old (pre-menopause, pre-hASC) or older than 55 years old (post-menopause, post-hASC). In this study, we provide proof of concept that the age-related ineffective functionality of ASCs can be reversed to improve their ability in promoting tissue repair. We found reduced estrogen receptor expression, decreased estrogen receptor activation, and reduced sensitivity to 17β-estradiol in post-hASCs. This correlated with decreased antioxidants (catalase and superoxide dismutase [SOD] expression) and increased oxidative stress compared with pre-hASCs. Increasing catalase expression in post-hASCs restored estrogen receptor (ER) expression and their functional capacity to promote tissue repair as shown in human skin ex vivo wound healing and in vivo mouse model of lung injury. Our results suggest that the consequences of 17β-estradiol decline on the function of hASCs may be reversible by changing the oxidative stress/antioxidant composition.
Collapse
Affiliation(s)
- Sharon J. Elliot
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Corresponding author: Sharon J. Elliot, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
| | - Paola Catanuto
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Simone Pereira-Simon
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Xiaomei Xia
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Seth Thaller
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Cheyanne R. Head
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Olivera Stojadinovic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marjana Tomic-Canic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marilyn K. Glassberg
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA,Corresponding author: Marilyn K. Glassberg, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
| |
Collapse
|
|
18
|
Chimento A, De Luca A, Avena P, De Amicis F, Casaburi I, Sirianni R, Pezzi V. Estrogen Receptors-Mediated Apoptosis in Hormone-Dependent Cancers. Int J Mol Sci 2022; 23:1242. [PMID: 35163166 PMCID: PMC8835409 DOI: 10.3390/ijms23031242] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα complex activates multiple pathways involved in both cell cycle progression and apoptotic cascade prevention, while E2/ERβ complex in many cases directs the cells to apoptosis. However, the exact mechanism of estrogen-induced tumor regression is not completely known. Nevertheless, ERs expression levels of specific splice variants and their cellular localization differentially affect outcome of estrogen-dependent tumors. The goal of this review is to provide a general overview of current knowledge on ERs-mediated apoptosis that occurs in main hormone dependent-cancers. Understanding the molecular mechanisms underlying the induction of ER-mediated cell death will be useful for the development of specific ligands capable of triggering apoptosis to counteract estrogen-dependent tumor growth.
Collapse
Affiliation(s)
- Adele Chimento
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Arianna De Luca
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Paola Avena
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Ivan Casaburi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Rosa Sirianni
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Vincenzo Pezzi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| |
Collapse
|
|
19
|
Sahebnasagh A, Saghafi F, Negintaji S, Hu T, Shabani-Borujeni M, Safdari M, Ghaleno HR, Miao L, Qi Y, Wang M, Liao P, Sureda A, Simal-Gándara J, Nabavi SM, Xiao J. Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies. Curr Med Chem 2022; 29:1561-1595. [PMID: 34238142 DOI: 10.2174/0929867328666210707194543] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/05/2021] [Accepted: 05/15/2021] [Indexed: 02/08/2023]
Abstract
In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this "doubleedged sword" in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.
Collapse
Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sina Negintaji
- Student Research Committee, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Tingyan Hu
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Mojtaba Shabani-Borujeni
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Safdari
- Department of Orthopedic Surgery, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hassan Rezai Ghaleno
- Department of Surgery, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Lingchao Miao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao
| | - Yaping Qi
- Purdue Quantum Science and Engineering Institute, Purdue University, West Lafayette, IN 47907, USA
| | - Mingfu Wang
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Pan Liao
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress, and Balearic Islands Health Research Institute (IdISBa), University of the Balearic Islands, Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III, Madrid, Spain
| | - Jesus Simal-Gándara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
- International Research Centre for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
| |
Collapse
|
|
20
|
Adlanmerini M, Fontaine C, Gourdy P, Arnal JF, Lenfant F. Segregation of nuclear and membrane-initiated actions of estrogen receptor using genetically modified animals and pharmacological tools. Mol Cell Endocrinol 2022; 539:111467. [PMID: 34626731 DOI: 10.1016/j.mce.2021.111467] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/06/2021] [Accepted: 09/28/2021] [Indexed: 11/23/2022]
Abstract
Estrogen receptor alpha (ERα) and beta (ERβ) are members of the nuclear receptor superfamily, playing widespread functions in reproductive and non-reproductive tissues. Beside the canonical function of ERs as nuclear receptors, in this review, we summarize our current understanding of extra-nuclear, membrane-initiated functions of ERs with a specific focus on ERα. Over the last decade, in vivo evidence has accumulated to demonstrate the physiological relevance of this ERα membrane-initiated-signaling from mouse models to selective pharmacological tools. Finally, we discuss the perspectives and future challenges opened by the integration of extra-nuclear ERα signaling in physiology and pathology of estrogens.
Collapse
Affiliation(s)
- Marine Adlanmerini
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Coralie Fontaine
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Pierre Gourdy
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Jean-François Arnal
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Françoise Lenfant
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France.
| |
Collapse
|
|
21
|
Borek-Dorosz A, Pieczara A, Czamara K, Stojak M, Matuszyk E, Majzner K, Brzozowski K, Bresci A, Polli D, Baranska M. What is the ability of inflamed endothelium to uptake exogenous saturated fatty acids? A proof-of-concept study using spontaneous Raman, SRS and CARS microscopy. Cell Mol Life Sci 2022; 79:593. [PMID: 36380212 PMCID: PMC9666316 DOI: 10.1007/s00018-022-04616-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/16/2022] [Accepted: 10/27/2022] [Indexed: 11/17/2022]
Abstract
Endothelial cells (EC) in vivo buffer and regulate the transfer of plasma fatty acid (FA) to the underlying tissues. We hypothesize that inflammation could alter the functionality of the EC, i.e., their capacity and uptake of different FA. The aim of this work is to verify the functionality of inflamed cells by analyzing their ability to uptake and accumulate exogenous saturated FA. Control and inflammatory human microvascular endothelial cells stimulated in vitro with two deuterium-labeled saturated FA (D-FA), i.e., palmitic (D31-PA) and myristic (D27-MA) acids. Cells were measured both by spontaneous and stimulated Raman imaging to extract detailed information about uptaken FA, whereas coherent anti-Stokes Raman scattering and fluorescence imaging showed the global content of FA in cells. Additionally, we employed atomic force microscopy to obtain a morphological image of the cells. The results indicate that the uptake of D-FA in inflamed cells is dependent on their concentration and type. Cells accumulated D-FA when treated with a low concentration, and the effect was more pronounced for D27-MA, in normal cells, but even more so, in inflamed cells. In the case of D31-PA, a slightly increased uptake was observed for inflamed cells when administered at higher concentration. The results provide a better understanding of the EC inflammation and indicate the impact of the pathological state of the EC on their capacity to buffer fat. All the microscopic methods used showed complementarity in the analysis of FA uptake by EC, but each method recognized this process from a different perspective.
Collapse
Affiliation(s)
| | - Anna Pieczara
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Krzysztof Czamara
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Marta Stojak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Ewelina Matuszyk
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Katarzyna Majzner
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland ,Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Krzysztof Brzozowski
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland
| | - Arianna Bresci
- Physics Department, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milan, Italy
| | - Dario Polli
- Physics Department, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milan, Italy ,Institute for Photonics and Nanotechnology at CNR (CNR-IFN), Piazza Leonardo da Vinci, 32, 20133 Milan, Italy
| | - Malgorzata Baranska
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland ,Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| |
Collapse
|
|
22
|
Acconcia F, Fiocchetti M, Busonero C, Fernandez VS, Montalesi E, Cipolletti M, Pallottini V, Marino M. The extra-nuclear interactome of the estrogen receptors: implications for physiological functions. Mol Cell Endocrinol 2021; 538:111452. [PMID: 34500041 DOI: 10.1016/j.mce.2021.111452] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/19/2021] [Accepted: 09/02/2021] [Indexed: 02/07/2023]
Abstract
Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action of the steroid hormone 17β-estradiol (E2) through its estrogen receptors (i.e., ERα and ERβ). It is now clear that the E2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. The activation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasma membrane-localized ERs and is required for the coordination of gene expression, which ultimately controls the occurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locate at the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding the specificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localization unveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlying molecular details for such ERs signaling diversity in the perspective of the E2 physiological functions in the different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of the extra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactors and tried to extrapolate from available databases the ERα and ERβ extra-nuclear interactomes. Based on literature data, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in different sub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the context-dependent diversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility of the physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocytic compartments). Finally, we provide lists of proteins belonging to the potential ERα and ERβ extra-nuclear interactomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes in different tissues represents the next step for the research in the ERs field. Such characterization will be fundamental for the identification of novel druggable targets for the innovative treatment of ERs-related diseases.
Collapse
Affiliation(s)
- Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
| | - Marco Fiocchetti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Claudia Busonero
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Virginia Solar Fernandez
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Emiliano Montalesi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Valentina Pallottini
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
| |
Collapse
|
|
23
|
Ferreira C, Trindade F, Ferreira R, Neves JS, Leite-Moreira A, Amado F, Santos M, Nogueira-Ferreira R. Sexual dimorphism in cardiac remodeling: the molecular mechanisms ruled by sex hormones in the heart. J Mol Med (Berl) 2021; 100:245-267. [PMID: 34811581 DOI: 10.1007/s00109-021-02169-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 10/16/2021] [Accepted: 11/16/2021] [Indexed: 12/11/2022]
Abstract
Heart failure (HF) is growing in prevalence, due to an increase in aging and comorbidities. Heart failure with reduced ejection fraction (HFrEF) is more common in men, whereas heart failure with preserved ejection fraction (HFpEF) has a higher prevalence in women. However, the reasons for these epidemiological trends are not clear yet. Since HFpEF affects mostly postmenopausal women, sex hormones should play a pivotal role in HFpEF development. Furthermore, for HFpEF, contrary to HFrEF, effective therapeutic approaches are missing. Interestingly, studies evidenced that some therapies can have better results in women than in HFpEF men, emphasizing the necessity of understanding these observations at a molecular level. Thus, herein, we review the molecular mechanisms of estrogen and androgen actions in the heart in physiological conditions and explain how its dysregulation can lead to disease development. This clarification is essential in the road for an effective personalized management of HF, particularly HFpEF, towards the development of sex-specific therapeutic approaches.
Collapse
Affiliation(s)
- Cláudia Ferreira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Fábio Trindade
- Department of Surgery and Physiology, Cardiovascular R&D Center (UnIC), Faculty of Medicine, University of Porto, Porto, Portugal
| | - Rita Ferreira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - João Sérgio Neves
- Department of Surgery and Physiology, Cardiovascular R&D Center (UnIC), Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Adelino Leite-Moreira
- Department of Surgery and Physiology, Cardiovascular R&D Center (UnIC), Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Cardiothoracic Surgery, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Francisco Amado
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Mário Santos
- Department of Cardiology, Hospital Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
- UMIB - Unidade Multidisciplinar de Investigação Biomédica, ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Rita Nogueira-Ferreira
- Department of Surgery and Physiology, Cardiovascular R&D Center (UnIC), Faculty of Medicine, University of Porto, Porto, Portugal.
- UMIB - Unidade Multidisciplinar de Investigação Biomédica, ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
| |
Collapse
|
|
24
|
Estrogen Receptors as Molecular Targets of Endocrine Therapy for Glioblastoma. Int J Mol Sci 2021; 22:ijms222212404. [PMID: 34830286 PMCID: PMC8626012 DOI: 10.3390/ijms222212404] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 10/29/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Hormonal factors may participate in the development and progression of glioblastoma, the most aggressive primary tumor of the central nervous system. Many studies have been conducted on the possible involvement of estrogen receptors (ERs) in gliomas. Since there is a tendency for a reduced expression of ERs as the degree of malignancy of such tumors increases, it is important to understand the role of these receptors in the progression and treatment of this disease. ERs belong to the family of nuclear receptors, although they can also be in the plasmatic membrane, cytoplasm and mitochondria. They are classified as estrogen receptors alpha and beta (ER⍺ and ERβ), each with different isoforms that have a distinct function in the organism. ERs regulate multiple physiological and pathological processes through the activation of genomic and nongenomic pathways in the cell. Nevertheless, the role of each isoform in the development and progression of glioblastoma is not completely clear. Diverse in vitro and in vivo studies have shown encouraging results for endocrine therapy as a treatment for gliomas. At the same time, many questions have arisen concerning the nature of ERs as well as the mechanism of action of the proposed drugs. Hence, the aim of the current review is to describe the drugs that could possibly be utilized in endocrine therapy for the treatment of high-grade gliomas, analyze their interaction with ERs, and explore the involvement of these drugs and receptors in resistance to standard chemotherapy.
Collapse
|
|
25
|
Cirillo F, Pellegrino M, Talia M, Perrotta ID, Rigiracciolo DC, Spinelli A, Scordamaglia D, Muglia L, Guzzi R, Miglietta AM, De Francesco EM, Belfiore A, Maggiolini M, Lappano R. Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts. Clin Transl Med 2021; 11:e516. [PMID: 34841688 PMCID: PMC8567034 DOI: 10.1002/ctm2.516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild-type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC-1) is characterized by a unique expression of 46 kDa ERα splice variant (ERα46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ERα46 and IR occurs in BCAHC-1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high-throughput RNA sequencing analysis, we have also found that the cytokine interleukin-11 (IL11) is the main factor linking BCAHC-1 cells to breast cancer-associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC-1 cells regulates pro-tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM-1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC.
Collapse
Affiliation(s)
- Francesca Cirillo
- Department of PhysicsUniversity of CalabriaRendeItaly
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Michele Pellegrino
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Marianna Talia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Ida Daniela Perrotta
- Centre for Microscopy and Microanalysis, Transmission Electron Microscopy Laboratory, and Department of Biology, Ecology and Earth SciencesUniversity of CalabriaRendeItaly
| | | | - Asia Spinelli
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Domenica Scordamaglia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Lucia Muglia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Rita Guzzi
- Department of PhysicsUniversity of CalabriaRendeItaly
| | | | | | - Antonino Belfiore
- Department of Clinical and Experimental Medicine, University of CataniaGaribaldi‐Nesima HospitalCataniaItaly
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| |
Collapse
|
|
26
|
Avellaneda E, Lim A, Moeller S, Marquez J, Escalante Cobb P, Zambrano C, Patel A, Sanchez V, Godde K, Broussard C. HPTE-Induced Embryonic Thymocyte Death and Alteration of Differentiation Is Not Rescued by ERα or GPER Inhibition but Is Exacerbated by Concurrent TCR Signaling. Int J Mol Sci 2021; 22:ijms221810138. [PMID: 34576301 PMCID: PMC8471014 DOI: 10.3390/ijms221810138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/07/2021] [Accepted: 09/13/2021] [Indexed: 11/16/2022] Open
Abstract
Organochlorine pesticides, such as DDT, methoxychlor, and their metabolites, have been characterized as endocrine disrupting chemicals (EDCs); suggesting that their modes of action involve interaction with or abrogation of endogenous endocrine function. This study examined whether embryonic thymocyte death and alteration of differentiation induced by the primary metabolite of methoxychlor, HPTE, rely upon estrogen receptor binding and concurrent T cell receptor signaling. Estrogen receptor inhibition of ERα or GPER did not rescue embryonic thymocyte death induced by HPTE or the model estrogen diethylstilbestrol (DES). Moreover, adverse effects induced by HPTE or DES were worsened by concurrent TCR and CD2 differentiation signaling, compared with EDC exposure post-signaling. Together, these data suggest that HPTE- and DES-induced adverse effects on embryonic thymocytes do not rely solely on ER alpha or GPER but may require both. These results also provide evidence of a potential collaborative signaling mechanism between TCR and estrogen receptors to mediate adverse effects on embryonic thymocytes, as well as highlight a window of sensitivity that modulates EDC exposure severity.
Collapse
Affiliation(s)
- Eddie Avellaneda
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Atalie Lim
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Sara Moeller
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Jacqueline Marquez
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Priscilla Escalante Cobb
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Cristina Zambrano
- Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA;
| | - Aaditya Patel
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Victoria Sanchez
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - K. Godde
- Department of Sociology/Anthropology, University of La Verne, La Verne, CA 91750, USA;
| | - Christine Broussard
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
- Correspondence:
| |
Collapse
|
|
27
|
Joshua Cohen D, ElBaradie K, Boyan BD, Schwartz Z. Sex-specific effects of 17β-estradiol and dihydrotestosterone (DHT) on growth plate chondrocytes are dependent on both ERα and ERβ and require palmitoylation to translocate the receptors to the plasma membrane. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:159028. [PMID: 34416391 DOI: 10.1016/j.bbalip.2021.159028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/19/2021] [Accepted: 08/13/2021] [Indexed: 11/24/2022]
Abstract
Rat costochondral cartilage growth plate chondrocytes exhibit cell sex-specific responses to 17β-estradiol (E2), testosterone, and dihydrotestosterone (DHT). Mechanistically, E2 and DHT stimulate proliferation and extracellular matrix synthesis in chondrocytes from female and male rats, respectively, by signaling through protein kinase C (PKC) and phospholipase C (PLC). Estrogen receptors (ERα; ERβ) and androgen receptors (ARs) are present in both male and female cells, but it is not known whether they interact to elicit sex-specific signaling. We used specific agonists and antagonists of these receptors to examine the relative contributions of ERs and ARs in membrane-mediated E2 signaling in female chondrocytes and DHT signaling in male chondrocytes. PKC activity in female chondrocytes was stimulated by agonists of ERα and ERβ and required intact caveolae; PKC activity was inhibited by the E2 enantiomer and by an inhibitor of ERβ. Western blots of cell lysates co-immunoprecipitated for ERα suggested the formation of a complex containing both ERα and ERß with E2 treatment. DHT and DHT agonists activated PKC in male cells, while AR inhibition blocked the stimulatory effect of DHT on PKC. Inhibition of ERα and ERβ also blocked PKC activation by DHT. Western blots of whole-cell lysates, plasma membranes, and caveolae indicated the translocation of AR to the plasma membrane and specifically to caveolae with DHT treatment. These results suggest that E2 and DHT promote chondrocyte differentiation via the ability of ARs and ERs to form a complex. The results also indicate that intact caveolae and palmitoylation of the membrane receptor(s) or membrane receptor complex containing ERα and ERβ is required for E2 and DHT membrane-associated PKC activity in costochondral cartilage cells.
Collapse
Affiliation(s)
- D Joshua Cohen
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Khairat ElBaradie
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30033, USA
| | - Barbara D Boyan
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30033, USA.
| | - Zvi Schwartz
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| |
Collapse
|
|
28
|
Calfío C, Donoso F, Huidobro‐Toro JP. Anthocyanins Activate Membrane Estrogen Receptors With Nanomolar Potencies to Elicit a Nongenomic Vascular Response Via NO Production. J Am Heart Assoc 2021; 10:e020498. [PMID: 34350775 PMCID: PMC8475021 DOI: 10.1161/jaha.119.020498] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 06/11/2021] [Indexed: 11/16/2022]
Abstract
Background The vascular pharmacodynamics of anthocyanins is only partially understood. To examine whether the anthocyanin-induced vasorelaxation is related to membrane estrogen receptor activity, the role of ERα or GPER antagonism was ascertained on anthocyanins or 17-β estradiol-(E2) induced vasodilatations and NO production. Methods and Results The rat arterial mesenteric bed was perfused with either anthocyanins or corresponding 3-O-glycosides, or E2, to examine rapid concentration-dependent vasorelaxations. The luminally accessible fraction of NO in mesenteric perfusates before and after anthocyanins or E2 administration was quantified. Likewise, NO-DAF signal detected NO production in primary endothelial cells cultures incubated with anthocyanins or E2 in the absence and presence of ERα (ICI 182,780) or GPER (G-36) selective antagonists. Anthocyanins or corresponding glycosides elicited, within minutes, vasodilation with nanomolar potencies; half maximal anthocyanin response reached 50% to 60% efficacy, in contrast to acetylcholine. The vasorelaxation is of rapid onset and exclusively endothelium-dependent; NOS inhibition annulled the vasorelaxation. The delphinidin vascular response was not modified by 100 nmol/L atropine but significantly attenuated by joint application of ICI plus G-36 (52±4.6 versus 8.5±1.5%), revealing the role of membrane estrogen receptors. Moreover, the anthocyanin or E2-induced NO production was antagonized up to 70% by these antagonists. NO-DAF signal elicited by anthocyanins was annulled by NOS inhibition or by ICI plus G-36 addition. Conclusions The biomedical effect of anthocyanins or 3-O-glycosylates derivatives contained in naturally purple-colored foods or berries is due to increased NO production, and not to the phytochemical's antioxidant potential, highlighting the nutraceutical role of natural products in cardiovascular diseases.
Collapse
Affiliation(s)
- Camila Calfío
- Laboratorio de FarmacologíaDepartamento de BiologíaFacultad de Química y BiologíaUniversidad de Santiago de ChileSantiagoChile
| | - Francisca Donoso
- Laboratorio de FarmacologíaDepartamento de BiologíaFacultad de Química y BiologíaUniversidad de Santiago de ChileSantiagoChile
| | - J. Pablo Huidobro‐Toro
- Laboratorio de FarmacologíaDepartamento de BiologíaFacultad de Química y BiologíaUniversidad de Santiago de ChileSantiagoChile
- Centro Desarrollo de Nanociencias y Nanotecnología, CEDENNASantiagoChile
| |
Collapse
|
|
29
|
Abstract
Steroid hormones bind receptors in the cell nucleus and in the cell membrane. The most widely studied class of steroid hormone receptors are the nuclear receptors, named for their function as ligand-dependent transcription factors in the cell nucleus. Nuclear receptors, such as estrogen receptor alpha, can also be anchored to the plasma membrane, where they respond to steroids by activating signaling pathways independent of their function as transcription factors. Steroids can also bind integral membrane proteins, such as the G protein-coupled estrogen receptor. Membrane estrogen and progestin receptors have been cloned and characterized in vitro and influence the development and function of many organ systems. Membrane androgen receptors were cloned and characterized in vitro, but their function as androgen receptors in vivo is unresolved. We review the identity and function of membrane proteins that bind estrogens, progestins, and androgens. We discuss evidence that membrane glucocorticoid and mineralocorticoid receptors exist, and whether glucocorticoid and mineralocorticoid nuclear receptors act at the cell membrane. In many cases, integral membrane steroid receptors act independently of nuclear steroid receptors, even though they may share a ligand.
Collapse
Affiliation(s)
- Lindsey S Treviño
- Department of Population Sciences, Division of Health Equities, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Daniel A Gorelick
- Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Correspondence: Daniel A Gorelick, PhD, One Baylor Plaza, Alkek Building N1317.07, Houston, TX, 77030-3411, USA.
| |
Collapse
|
|
30
|
Single-cell immunoblotting resolves estrogen receptor-α isoforms in breast cancer. PLoS One 2021; 16:e0254783. [PMID: 34314438 PMCID: PMC8315538 DOI: 10.1371/journal.pone.0254783] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/28/2021] [Indexed: 12/18/2022] Open
Abstract
An array of isoforms of the nuclear estrogen receptor alpha (ER-α) protein contribute to heterogeneous response in breast cancer (BCa); yet, a single-cell analysis tool that distinguishes the full-length ER-α66 protein from the activation function-1 deficient ER-α46 isoform has not been reported. Specific detection of protein isoforms is a gap in single-cell analysis tools, as the de facto standard immunoassay requires isoform-specific antibody probes. Consequently, to scrutinize hormone response heterogeneity among BCa tumor cells, we develop a precision tool to specifically measure ER-α66, ER- α46, and eight ER-signaling proteins with single-cell resolution in the highly hetero-clonal MCF-7 BCa cell line. With a literature-validated pan-ER immunoprobe, we distinguish ER-α66 from ER-α46 in each individual cell. We identify ER-α46 in 5.5% of hormone-sensitive (MCF-7) and 4.2% of hormone-insensitive (MDA-MB-231) BCa cell lines. To examine whether the single-cell immunoblotting can capture cellular responses to hormones, we treat cells with tamoxifen and identify different sub-populations of ER-α46: (i) ER-α46 induces phospho-AKT at Ser473, (ii) S6-ribosomal protein, an upstream ER target, activates both ER-α66 and ER-α46 in MCF-7 cells, and (iii) ER-α46 partitions MDA-MB-231 subpopulations, which are responsive to tamoxifen. Unlike other single-cell immunoassays, multiplexed single-cell immunoblotting reports–in the same cell–tamoxifen effects on ER signaling proteins and on distinct isoforms of the ER-α protein.
Collapse
|
|
31
|
Rusidzé M, Adlanmérini M, Chantalat E, Raymond-Letron I, Cayre S, Arnal JF, Deugnier MA, Lenfant F. Estrogen receptor-α signaling in post-natal mammary development and breast cancers. Cell Mol Life Sci 2021; 78:5681-5705. [PMID: 34156490 PMCID: PMC8316234 DOI: 10.1007/s00018-021-03860-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/12/2021] [Accepted: 05/19/2021] [Indexed: 12/16/2022]
Abstract
17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice.
Collapse
Affiliation(s)
- Mariam Rusidzé
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - Marine Adlanmérini
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - Elodie Chantalat
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - I Raymond-Letron
- LabHPEC et Institut RESTORE, Université de Toulouse, CNRS U-5070, EFS, ENVT, Inserm U1301, Toulouse, France
| | - Surya Cayre
- Department of Cell Biology and Cancer, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR144, Paris, France
| | - Jean-François Arnal
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - Marie-Ange Deugnier
- Department of Cell Biology and Cancer, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR144, Paris, France
| | - Françoise Lenfant
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France.
| |
Collapse
|
|
32
|
Reyes-García J, Montaño LM, Carbajal-García A, Wang YX. Sex Hormones and Lung Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1304:259-321. [PMID: 34019274 DOI: 10.1007/978-3-030-68748-9_15] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammation is a characteristic marker in numerous lung disorders. Several immune cells, such as macrophages, dendritic cells, eosinophils, as well as T and B lymphocytes, synthetize and release cytokines involved in the inflammatory process. Gender differences in the incidence and severity of inflammatory lung ailments including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), lung cancer (LC), and infectious related illnesses have been reported. Moreover, the effects of sex hormones on both androgens and estrogens, such as testosterone (TES) and 17β-estradiol (E2), driving characteristic inflammatory patterns in those lung inflammatory diseases have been investigated. In general, androgens seem to display anti-inflammatory actions, whereas estrogens produce pro-inflammatory effects. For instance, androgens regulate negatively inflammation in asthma by targeting type 2 innate lymphoid cells (ILC2s) and T-helper (Th)-2 cells to attenuate interleukin (IL)-17A-mediated responses and leukotriene (LT) biosynthesis pathway. Estrogens may promote neutrophilic inflammation in subjects with asthma and COPD. Moreover, the activation of estrogen receptors might induce tumorigenesis. In this chapter, we summarize the most recent advances in the functional roles and associated signaling pathways of inflammatory cellular responses in asthma, COPD, PF, LC, and newly occurring COVID-19 disease. We also meticulously deliberate the influence of sex steroids on the development and progress of these common and severe lung diseases.
Collapse
Affiliation(s)
- Jorge Reyes-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico.,Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Luis M Montaño
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico
| | - Abril Carbajal-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico
| | - Yong-Xiao Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
| |
Collapse
|
|
33
|
Gibson DA, Esnal-Zufiaurre A, Bajo-Santos C, Collins F, Critchley HOD, Saunders PTK. Profiling the expression and function of oestrogen receptor isoform ER46 in human endometrial tissues and uterine natural killer cells. Hum Reprod 2021; 35:641-651. [PMID: 32108901 PMCID: PMC7105323 DOI: 10.1093/humrep/dez306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
STUDY QUESTION Does the oestrogen receptor isoform, ER46, contribute to regulation of endometrial function? SUMMARY ANSWER ER46 is expressed in endometrial tissues, is the predominant ER isoform in first trimester decidua and is localised to the cell membrane of uterine natural killer (uNK) cells where activation of ER46 increases cell motility. WHAT IS KNOWN ALREADY Oestrogens acting via their cognate receptors are essential regulators of endometrial function and play key roles in establishment of pregnancy. ER46 is a 46-kDa truncated isoform of full length ERα (ER66, encoded by ESR1) that contains both ligand- and DNA-binding domains. Expression of ER46 in the human endometrium has not been investigated previously. ER46 is located at the cell membrane of peripheral blood leukocytes and mediates rapid responses to oestrogens. uNK cells are a phenotypically distinct (CD56brightCD16-) population of tissue-resident immune cells that regulate vascular remodelling within the endometrium and decidua. We have shown that oestrogens stimulate rapid increases in uNK cell motility. Previous characterisation of uNK cells suggests they are ER66-negative, but expression of ER46 has not been characterised. We hypothesise that uNK cells express ER46 and that rapid responses to oestrogens are mediated via this receptor. STUDY DESIGN, SIZE, DURATION This laboratory-based study used primary human endometrial (n = 24) and decidual tissue biopsies (n = 30) as well as uNK cells which were freshly isolated from first trimester human decidua (n = 18). PARTICIPANTS/MATERIALS, SETTING, METHODS Primary human endometrial and first trimester decidual tissue biopsies were collected using methods approved by the local institutional ethics committee (LREC/05/51104/12 and LREC/10/51402/59). The expression of ERs (ER66, ER46 and ERβ) was assessed by quantitative PCR, western blot and immunohistochemistry. uNK cells were isolated from first-trimester human decidua by magnetic bead sorting. Cell motility of uNK cells was measured by live cell imaging: cells were treated with 17β-oestradiol conjugated to bovine serum albumin (E2-BSA, 10 nM equivalent), the ERβ-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nM) or dimethylsulphoxide vehicle control. MAIN RESULTS AND THE ROLE OF CHANCE ER46 was detected in proliferative and secretory phase tissues by western blot and was the predominant ER isoform in first-trimester decidua samples. Immunohistochemistry revealed that ER46 was co-localised with ER66 in cell nuclei during the proliferative phase but detected in both the cytoplasm and cell membrane of stromal cells in the secretory phase and in decidua. Triple immunofluorescence staining of decidua tissues identified expression of ER46 in the cell membrane of CD56-positive uNK cells which were otherwise ER66-negative. Profiling of isolated uNK cells confirmed expression of ER46 by quantitative PCR and western blot and localised ER46 protein to the cell membrane by immunocytochemistry. Functional analysis of isolated uNK cells using live cell imaging demonstrated that activation of ER46 with E2-BSA significantly increased uNK cell motility. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Expression pattern in endometrial tissue was only determined using samples from proliferative and secretory phases. Assessment of first trimester decidua samples was from a range of gestational ages, which may have precluded insights into gestation-specific changes in these tissues. Our results are based on in vitro responses of primary human cells and we cannot be certain that similar mechanisms occur in situ. WIDER IMPLICATIONS OF THE FINDINGS E2 is an essential regulator of reproductive competence. This study provides the first evidence for expression of ER46 in the human endometrium and decidua of early pregnancy. We describe a mechanism for regulating the function of human uNK cells via expression of ER46 and demonstrate that selective targeting with E2-BSA regulates uNK cell motility. These novel findings identify a role for ER46 in the human endometrium and provide unique insight into the importance of membrane-initiated signalling in modulating the impact of E2 on uNK cell function in women. Given the importance of uNK cells to regulating vascular remodelling in early pregnancy and the potential for selective targeting of ER46, this may be an attractive future therapeutic target in the treatment of reproductive disorders. STUDY FUNDING/COMPETING INTEREST(S) These studies were supported by Medical Research Council (MRC) Programme Grants G1100356/1 and MR/N024524/1 to PTKS. H.O.D.C. was supported by MRC grant G1002033. The authors declare no competing interests related to the published work.
Collapse
Affiliation(s)
- Douglas A Gibson
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | | | - Cristina Bajo-Santos
- Department of Cancer Research Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Frances Collins
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | | | | |
Collapse
|
|
34
|
Niță AR, Knock GA, Heads RJ. Signalling mechanisms in the cardiovascular protective effects of estrogen: With a focus on rapid/membrane signalling. Curr Res Physiol 2021; 4:103-118. [PMID: 34746830 PMCID: PMC8562205 DOI: 10.1016/j.crphys.2021.03.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/22/2022] Open
Abstract
In modern society, cardiovascular disease remains the biggest single threat to life, being responsible for approximately one third of worldwide deaths. Male prevalence is significantly higher than that of women until after menopause, when the prevalence of CVD increases in females until it eventually exceeds that of men. Because of the coincidence of CVD prevalence increasing after menopause, the role of estrogen in the cardiovascular system has been intensively researched during the past two decades in vitro, in vivo and in observational studies. Most of these studies suggested that endogenous estrogen confers cardiovascular protective and anti-inflammatory effects. However, clinical studies of the cardioprotective effects of hormone replacement therapies (HRT) not only failed to produce proof of protective effects, but also revealed the potential harm estrogen could cause. The "critical window of hormone therapy" hypothesis affirms that the moment of its administration is essential for positive treatment outcomes, pre-menopause (3-5 years before menopause) and immediately post menopause being thought to be the most appropriate time for intervention. Since many of the cardioprotective effects of estrogen signaling are mediated by effects on the vasculature, this review aims to discuss the effects of estrogen on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) with a focus on the role of estrogen receptors (ERα, ERβ and GPER) in triggering the more recently discovered rapid, or membrane delimited (non-genomic), signaling cascades that are vital for regulating vascular tone, preventing hypertension and other cardiovascular diseases.
Collapse
Affiliation(s)
- Ana-Roberta Niță
- School of Bioscience Education, Faculty of Life Sciences and Medicine, King’s College London, UK
| | - Greg A. Knock
- School of Bioscience Education, Faculty of Life Sciences and Medicine, King’s College London, UK
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
| | - Richard J. Heads
- School of Bioscience Education, Faculty of Life Sciences and Medicine, King’s College London, UK
- Cardiovascular Research Section, King’s BHF Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King’s College London, UK
| |
Collapse
|
|
35
|
Sexual hormones and diabetes: The impact of estradiol in pancreatic β cell. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021. [PMID: 33832654 DOI: 10.1016/bs.ircmb.2021.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/13/2023]
Abstract
Diabetes is one of the most prevalent metabolic diseases and its incidence is increasing throughout the world. Data from World Health Organization (WHO) point-out that diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation and estimated 1.6 million deaths were directly caused by it in 2016. Population studies show that the incidence of this disease increases in women after menopause, when the production of estrogen is decreasing in them. Knowing the impact that estrogenic signaling has on insulin-secreting β cells is key to prevention and design of new therapeutic targets. This chapter explores the role of estrogen and their receptors in the regulation of insulin secretion and biosynthesis, proliferation, regeneration and survival in pancreatic β cells. In addition, delves into the genetic animal models developed and its application for the specific study of the different estrogen signaling pathways. Finally, discusses the impact of menopause and hormone replacement therapy on pancreatic β cell function.
Collapse
|
|
36
|
Lynch S, Boyett JE, Smith MR, Giordano-Mooga S. Sex Hormone Regulation of Proteins Modulating Mitochondrial Metabolism, Dynamics and Inter-Organellar Cross Talk in Cardiovascular Disease. Front Cell Dev Biol 2021; 8:610516. [PMID: 33644031 PMCID: PMC7905018 DOI: 10.3389/fcell.2020.610516] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death in the U.S. and worldwide. Sex-related disparities have been identified in the presentation and incidence rate of CVD. Mitochondrial dysfunction plays a role in both the etiology and pathology of CVD. Recent work has suggested that the sex hormones play a role in regulating mitochondrial dynamics, metabolism, and cross talk with other organelles. Specifically, the female sex hormone, estrogen, has both a direct and an indirect role in regulating mitochondrial biogenesis via PGC-1α, dynamics through Opa1, Mfn1, Mfn2, and Drp1, as well as metabolism and redox signaling through the antioxidant response element. Furthermore, data suggests that testosterone is cardioprotective in males and may regulate mitochondrial biogenesis through PGC-1α and dynamics via Mfn1 and Drp1. These cell-signaling hubs are essential in maintaining mitochondrial integrity and cell viability, ultimately impacting CVD survival. PGC-1α also plays a crucial role in inter-organellar cross talk between the mitochondria and other organelles such as the peroxisome. This inter-organellar signaling is an avenue for ameliorating rampant ROS produced by dysregulated mitochondria and for regulating intrinsic apoptosis by modulating intracellular Ca2+ levels through interactions with the endoplasmic reticulum. There is a need for future research on the regulatory role of the sex hormones, particularly testosterone, and their cardioprotective effects. This review hopes to highlight the regulatory role of sex hormones on mitochondrial signaling and their function in the underlying disparities between men and women in CVD.
Collapse
Affiliation(s)
- Shannon Lynch
- Biomedical Sciences Program, Graduate School, University of Alabama at Birmingham, Birmingham, AL, United States
| | - James E Boyett
- Biomedical Sciences Program, Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, AL, United States
| | - M Ryan Smith
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA, United States
| | - Samantha Giordano-Mooga
- Biomedical Sciences Program, Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, AL, United States
| |
Collapse
|
|
37
|
Zheng S, Wu L, Fan C, Lin J, Zhang Y, Simoncini T, Fu X. The role of Gα protein signaling in the membrane estrogen receptor-mediated signaling. Gynecol Endocrinol 2021; 37:2-9. [PMID: 33412963 DOI: 10.1080/09513590.2020.1851674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Estrogens exert rapid, extranuclear effects by their action on the plasma membrane estrogen receptors (mERs). Gα protein associated with the cell membrane is involved in many important processes regulated by estrogens. However, the Gα's role in the mER-mediated signaling and the signaling pathways involved are poorly understood. This review aims to outline the Gα's role in the mER-mediated signaling. Immunoblotting, immunofluorescence, co-immunoprecipitation, and RNA interference were carried out using vascular endothelial cells (ECs) and human breast carcinoma cell lines as experimental models. Electrophysiology and immunocytochemistry were carried out using guinea pigs as animal models. Recent advances suggest that the signaling of mERα through Gα is required for vascular EC migration or endothelial H2S release, while Gα13 is involved in estrogen-induced breast cancer cell invasion. Besides, the Gαq-coupled PLC-PKC-PKA pathway is critical for the neural regulation of energy homeostasis. This review summarizes the contributions of Gα to mER-mediated signaling, including cardiovascular protection, breast cancer metastasis, neural regulation of homeostatic functions, and osteogenesis.
Collapse
Affiliation(s)
- Shuhui Zheng
- Research Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lin Wu
- Department of Cardiology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Chao Fan
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China
| | - Jingxia Lin
- Department of Blood Transfusion, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yaxing Zhang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tommaso Simoncini
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy
| | - Xiaodong Fu
- Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China
| |
Collapse
|
|
38
|
Chimento A, De Luca A, Nocito MC, Avena P, La Padula D, Zavaglia L, Pezzi V. Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis. Cells 2020; 9:cells9092115. [PMID: 32957524 PMCID: PMC7563107 DOI: 10.3390/cells9092115] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/15/2020] [Accepted: 09/15/2020] [Indexed: 12/11/2022] Open
Abstract
Estrogen signaling plays important roles in testicular functions and tumorigenesis. Fifteen years ago, it was discovered that a member of the G protein-coupled receptor family, GPR30, which binds also with high affinity to estradiol and is responsible, in part, for the rapid non-genomic actions of estrogens. GPR30, renamed as GPER, was detected in several tissues including germ cells (spermatogonia, spermatocytes, spermatids) and somatic cells (Sertoli and Leydig cells). In our previous review published in 2014, we summarized studies that evidenced a role of GPER signaling in mediating estrogen action during spermatogenesis and testis development. In addition, we evidenced that GPER seems to be involved in modulating estrogen-dependent testicular cancer cell growth; however, the effects on cell survival and proliferation depend on specific cell type. In this review, we update the knowledge obtained in the last years on GPER roles in regulating physiological functions of testicular cells and its involvement in neoplastic transformation of both germ and somatic cells. In particular, we will focus our attention on crosstalk among GPER signaling, classical estrogen receptors and other nuclear receptors involved in testis physiology regulation.
Collapse
Affiliation(s)
- Adele Chimento
- Correspondence: (A.C.); (V.P.); Tel.: +39-0984-493184 (A.C.); +39-0984-493148 (V.P.)
| | | | | | | | | | | | - Vincenzo Pezzi
- Correspondence: (A.C.); (V.P.); Tel.: +39-0984-493184 (A.C.); +39-0984-493148 (V.P.)
| |
Collapse
|
|
39
|
Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy. Int J Mol Sci 2020; 21:ijms21124349. [PMID: 32570961 PMCID: PMC7352873 DOI: 10.3390/ijms21124349] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/10/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022] Open
Abstract
Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal–fetal exchanges of respiratory gases and to provide sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remain incompletely understood, but this is associated with elevated estrogens, which stimulate specific estrogen receptor (ER)-dependent vasodilator production in the uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. The activation of these three ERs by estrogens enhances the endothelial production of nitric oxide (NO), which has been shown to play a key role in uterine vasodilation during pregnancy. However, the local blockade of NO biosynthesis only partially attenuates estrogen-induced and pregnancy-associated uterine vasodilation, suggesting that mechanisms other than NO exist to mediate uterine vasodilation. In this review, we summarize the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a “new” UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.
Collapse
|
|
40
|
Thiebaut C, Konan HP, Guerquin MJ, Chesnel A, Livera G, Le Romancer M, Dumond H. The Role of ERα36 in Development and Tumor Malignancy. Int J Mol Sci 2020; 21:E4116. [PMID: 32526980 PMCID: PMC7312586 DOI: 10.3390/ijms21114116] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/03/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023] Open
Abstract
Estrogen nuclear receptors, represented by the canonical forms ERα66 and ERβ1, are the main mediators of the estrogen-dependent pathophysiology in mammals. However, numerous isoforms have been identified, stimulating unconventional estrogen response pathways leading to complex cellular and tissue responses. The estrogen receptor variant, ERα36, was cloned in 2005 and is mainly described in the literature to be involved in the progression of mammary tumors and in the acquired resistance to anti-estrogen drugs, such as tamoxifen. In this review, we will first specify the place that ERα36 currently occupies within the diversity of nuclear and membrane estrogen receptors. We will then report recent data on the impact of ERα36 expression and/or activity in normal breast and testicular cells, but also in different types of tumors including mammary tumors, highlighting why ERα36 can now be considered as a marker of malignancy. Finally, we will explain how studying the regulation of ERα36 expression could provide new clues to counteract resistance to cancer treatments in hormone-sensitive tumors.
Collapse
Affiliation(s)
- Charlène Thiebaut
- Université de Lorraine, CNRS, CRAN, F-54000 Nancy, France; (C.T.); (A.C.)
| | - Henri-Philippe Konan
- Université de Lyon, F-69000 Lyon, France; (H.-P.K.); (M.L.R.)
- INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Marie-Justine Guerquin
- Laboratory of Development of the Gonads, UMRE008 Genetic Stability Stem Cells and Radiation, Université de Paris, Université Paris Saclay, CEA, F-92265 Fontenay aux Roses, France; (M.-J.G.); (G.L.)
| | - Amand Chesnel
- Université de Lorraine, CNRS, CRAN, F-54000 Nancy, France; (C.T.); (A.C.)
| | - Gabriel Livera
- Laboratory of Development of the Gonads, UMRE008 Genetic Stability Stem Cells and Radiation, Université de Paris, Université Paris Saclay, CEA, F-92265 Fontenay aux Roses, France; (M.-J.G.); (G.L.)
| | - Muriel Le Romancer
- Université de Lyon, F-69000 Lyon, France; (H.-P.K.); (M.L.R.)
- INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Hélène Dumond
- Université de Lorraine, CNRS, CRAN, F-54000 Nancy, France; (C.T.); (A.C.)
| |
Collapse
|
|
41
|
The Impact of Estrogen Receptor in Arterial and Lymphatic Vascular Diseases. Int J Mol Sci 2020; 21:ijms21093244. [PMID: 32375307 PMCID: PMC7247322 DOI: 10.3390/ijms21093244] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/17/2020] [Accepted: 04/29/2020] [Indexed: 12/12/2022] Open
Abstract
The lower incidence of cardiovascular diseases in pre-menopausal women compared to men is well-known documented. This protection has been largely attributed to the protective effect of estrogens, which exert many beneficial effects against arterial diseases, including vasodilatation, acceleration of healing in response to arterial injury, arterial collateral growth and atheroprotection. More recently, with the visualization of the lymphatic vessels, the impact of estrogens on lymphedema and lymphatic diseases started to be elucidated. These estrogenic effects are mediated not only by the classic nuclear/genomic actions via the specific estrogen receptor (ER) α and β, but also by rapid extra-nuclear membrane-initiated steroid signaling (MISS). The ERs are expressed by endothelial, lymphatic and smooth muscle cells in the different vessels. In this review, we will summarize the complex vascular effects of estrogens and selective estrogen receptor modulators (SERMs) that have been described using different transgenic mouse models with selective loss of ERα function and numerous animal models of vascular and lymphatic diseases.
Collapse
|
|
42
|
Pastore MB, Landeros RV, Chen DB, Magness RR. Structural analysis of estrogen receptors: interaction between estrogen receptors and cav-1 within the caveolae†. Biol Reprod 2020; 100:495-504. [PMID: 30137221 DOI: 10.1093/biolre/ioy188] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 08/13/2018] [Accepted: 08/20/2018] [Indexed: 01/12/2023] Open
Abstract
Pregnancy is a physiologic state of substantially elevated estrogen biosynthesis that maintains vasodilator production by uterine artery endothelial cells (P-UAECs) and thus uterine perfusion. Estrogen receptors (ER-α and ER-β; ESR1 and ESR2) stimulate nongenomic rapid vasodilatory responses partly through activation of endothelial nitric oxide synthase (eNOS). Rapid estrogenic responses are initiated by the ∼4% ESRs localized to the plasmalemma of endothelial cells. Caveolin-1 (Cav-1) interactions within the caveolae are theorized to influence estrogenic effects mediated by both ESRs. Hypothesis: Both ESR1 and ESR2 display similar spatial partitioning between the plasmalemma and nucleus of UAECs and have similar interactions with Cav-1 at the plasmalemma. Using transmission electron microscopy, we observed numerous caveolae structures in UAECs, while immunogold labeling and subcellular fractionations identified ESR1 and ESR2 in three subcellular locations: membrane, cytosol, and nucleus. Bioinformatics approaches to analyze ESR1 and ESR2 transmembrane domains identified no regions that facilitate ESR interaction with plasmalemma. However, sucrose density centrifugation and Cav-1 immunoisolation columns uniquely demonstrated very high protein-protein association only between ESR1, but not ESR2, with Cav-1. These data demonstrate (1) both ESRs localize to the plasmalemma, cytosol and nucleus; (2) neither ESR1 nor ESR2 contain a classic region that crosses the plasmalemma to facilitate attachment; and (3) ESR1, but not ESR2, can be detected in the caveolar subcellular domain demonstrating ESR1 is the only ESR bound in close proximity to Cav-1 and eNOS within this microdomain. Lack of protein-protein interaction between Cav-1 and ESR2 demonstrates a novel independent association of these proteins at the plasmalemma.
Collapse
Affiliation(s)
- Mayra B Pastore
- Department of Obstetrics and Gynecology Perinatal Research Labs, University of Wisconsin-Madison, Madison, Wisconsin, USA.,Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA
| | - Rosalina Villalon Landeros
- Department of Obstetrics and Gynecology Perinatal Research Labs, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Dong-Bao Chen
- Department of Obstetrics and Gynecology University of California Irvine, Irvine, California, USA
| | - Ronald R Magness
- Department of Obstetrics and Gynecology Perinatal Research Labs, University of Wisconsin-Madison, Madison, Wisconsin, USA.,Department of Obstetrics and Gynecology University of South Florida, Tampa, Florida, USA
| |
Collapse
|
|
43
|
Tunc E, Eve AA, Madak-Erdogan Z. Coronary Microvascular Dysfunction and Estrogen Receptor Signaling. Trends Endocrinol Metab 2020; 31:228-238. [PMID: 31787492 DOI: 10.1016/j.tem.2019.11.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 10/14/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023]
Abstract
Chest pain with non-obstructive coronary artery disease (NOCAD) occurs more frequently in women than in men and is mainly related to coronary microvascular disease (CMD). The majority of CMD patients are postmenopausal women, suggesting a role for lack of estrogens in the development and progression of CMD. Patients are often discharged without a clear treatment plan due to the limited understanding of etiology and diagnostic parameters of CMD and have significantly higher rates of future cardiovascular events. Thus, there is a need for a better understanding of the underlying biology, and CMD-specific diagnostic tests and therapies. In this article, we reviewed recent studies on CMD, estrogen action in coronary microvasculature, and diagnosis and treatment options for CMD in postmenopausal women.
Collapse
Affiliation(s)
- Elif Tunc
- Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Alicia Arredondo Eve
- Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Zeynep Madak-Erdogan
- Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
| |
Collapse
|
|
44
|
Amenyogbe E, Chen G, Wang Z, Lu X, Lin M, Lin AY. A Review on Sex Steroid Hormone Estrogen Receptors in Mammals and Fish. Int J Endocrinol 2020; 2020:5386193. [PMID: 32089683 PMCID: PMC7029290 DOI: 10.1155/2020/5386193] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/04/2019] [Accepted: 11/19/2019] [Indexed: 12/26/2022] Open
Abstract
Steroid hormones play essential roles in the reproductive biology of vertebrates. Estrogen exercises its effect through estrogen receptors and is not only a female reproductive hormone but acts virtually in all vertebrates, including fish, and is involved in the physiological and pathological states in all males and females. Estrogen has been implicated in mandible conservation and circulatory and central nervous systems as well as the reproductive system. This review intended to understand the structure, function, binding affinities, and activations of estrogens and estrogen receptors and to discuss the understanding of the role of sex steroid hormone estrogen receptors in mammals and fish.
Collapse
Affiliation(s)
- Eric Amenyogbe
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquaculture in the South China Sea for Aquatic Economic Animal of Guangdong Higher Education Institutes, Laboratory of Fish Aquaculture, Zhanjiang 524025, China
| | - Gang Chen
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquaculture in the South China Sea for Aquatic Economic Animal of Guangdong Higher Education Institutes, Laboratory of Fish Aquaculture, Zhanjiang 524025, China
| | - Zhongliang Wang
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquaculture in the South China Sea for Aquatic Economic Animal of Guangdong Higher Education Institutes, Laboratory of Fish Aquaculture, Zhanjiang 524025, China
| | - Xiaoying Lu
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquaculture in the South China Sea for Aquatic Economic Animal of Guangdong Higher Education Institutes, Laboratory of Fish Aquaculture, Zhanjiang 524025, China
| | - Mingde Lin
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquaculture in the South China Sea for Aquatic Economic Animal of Guangdong Higher Education Institutes, Laboratory of Fish Aquaculture, Zhanjiang 524025, China
| | - Ai Ying Lin
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquaculture in the South China Sea for Aquatic Economic Animal of Guangdong Higher Education Institutes, Laboratory of Fish Aquaculture, Zhanjiang 524025, China
| |
Collapse
|
|
45
|
Pagano MT, Ortona E, Dupuis ML. A Role for Estrogen Receptor alpha36 in Cancer Progression. Front Endocrinol (Lausanne) 2020; 11:506. [PMID: 32849292 PMCID: PMC7411082 DOI: 10.3389/fendo.2020.00506] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 06/24/2020] [Indexed: 12/22/2022] Open
Abstract
Estrogen receptor α (ERα) functions as a ligand dependent transcription factor that directly binds specific estrogen responsive elements, thus regulating the transcription of estrogen sensitive genes. ERα has also been shown to be associated with the plasma membrane (membrane associated ERα, mERα), concentrated in lipid rafts, plasma membrane microdomains with a distinct lipid composition, where it transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein (MAP) kinase signaling pathway. Two isoforms of ERα have been described: the "traditional" ERα66 (66 kDa) and a lower molecular weight variant: the ERα46 (46 kDa). More recently, a novel ERα variant with a molecular mass of 36 kDa (ERα36) has been discovered. Notably, ERα36 has been found expressed in different human tumor cells, including both ER- positive and ER- negative breast cancer cells. Estrogen signaling at the cell membrane via ERα36 appears as capable of activating multiple pathways of importance for cancer aggressiveness and metastatic potential. The presence of serum autoantibodies reacting with mERα (anti-ERα Abs) in a large percentage of patients with breast cancer has recently been reported by our group. These anti-ERα Abs seem to act as estrogen agonists rapidly triggering MAP kinase pathway activation thus inducing tumor cell proliferation and overcoming cell resistance to anti-estrogen drug tamoxifen. In this review, we describe the involvement of ERα36 in different tumors. We also report the potential pathogenetic activity of anti-ERα Abs and their implication in drug resistance.
Collapse
|
|
46
|
Filiponi M, Gougoura SG, Befani C, Bargiota Α, Liakos P, Koukoulis GN. 17-β estradiol attenuates the pro-oxidant activity of corticotropin-releasing hormone in macroendothelial cells. Cell Biol Int 2019; 43:1407-1415. [PMID: 31141240 DOI: 10.1002/cbin.11188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/25/2019] [Indexed: 01/24/2023]
Abstract
Corticotropin-releasing hormone, which is the predominant regulator of neuroendocrine responses to stress, attenuates inflammation through stimulation of glucocorticoid release. Enhanced corticotropin-releasing hormone expression has been detected in inflammatory cells of the vascular endothelium, where it acts as a local regulator of endothelial redox homeostasis. Estrogens have beneficial effects on endothelial integrity and function, though the mechanism underlying their antioxidative effect remains as yet largely unknown. We therefore investigated the effect of 17β-estradiol on pro-oxidant action of corticotropin-releasing hormone in vitro in macroendothelial cells, and, more specifically, the role of 17β-estradiol on corticotropin-releasing hormone-induced activities/release of the antioxidant enzymes namely, endothelial nitric oxide synthase, superoxide dismutase, catalase, and glutathione. We observed that 17β-estradiol abolished the stimulatory effect of corticotropin-releasing hormone on intracellular reactive oxygen species levels and counteracted its inhibitory effect on endothelial nitric oxide synthase activity and nitric oxide release. In addition, 17β-estradiol significantly induced superoxide dismutase and catalase activity, an effect that was not significantly influenced by corticotropin-releasing hormone. Finally, 17β-estradiol significantly increased glutathione levels and the glutathione/glutathione + glutathione disulfide ratio, an action that was partially blocked by corticotropin-releasing hormone. Our results reveal that 17β-estradiol counterbalances corticotropin-releasing hormone-mediated pro-inflammatory action and thereby maintains the physiological threshold of the endothelial cell redox environment. These observations may be of importance, considering the protective role of estrogen in the development of atherosclerosis.
Collapse
Affiliation(s)
- Maria Filiponi
- Department of Endocrinology and Metabolic Diseases, Research Laboratory, Larissa University Hospital, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Sofia G Gougoura
- Department of Endocrinology and Metabolic Diseases, Research Laboratory, Larissa University Hospital, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Christina Befani
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Αlexandra Bargiota
- Department of Endocrinology and Metabolic Diseases, Research Laboratory, Larissa University Hospital, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Panagiotis Liakos
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - George N Koukoulis
- Department of Endocrinology and Metabolic Diseases, Research Laboratory, Larissa University Hospital, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| |
Collapse
|
|
47
|
Yang Q, Zhao J, Zhang W, Chen D, Wang Y. Aberrant alternative splicing in breast cancer. J Mol Cell Biol 2019; 11:920-929. [PMID: 31065692 PMCID: PMC6884705 DOI: 10.1093/jmcb/mjz033] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 02/19/2019] [Accepted: 03/03/2019] [Indexed: 12/11/2022] Open
Abstract
Alternative splicing is critical for human gene expression regulation, which plays a determined role in expanding the diversity of functional proteins. Importantly, alternative splicing is a hallmark of cancer and a potential target for cancer therapeutics. Based on the statistical data, breast cancer is one of the top leading causes of cancer-related deaths in women worldwide. Strikingly, alternative splicing is closely associated with breast cancer development. Here, we seek to provide a general review of the relationship between alternative splicing and breast cancer. We introduce the process of alternative splicing and its regulatory role in cancers. In addition, we highlight the functions of aberrant alternative splicing and mutations of splicing factors in breast cancer progression. Moreover, we discuss the role of alternative splicing in cancer drug resistance and the potential of being targets for cancer therapeutics.
Collapse
Affiliation(s)
- Quan Yang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Jinyao Zhao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Wenjing Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Dan Chen
- Department of Pathology, First Affiliated Hospital, Dalian Medical University, Dalian 116044, China
| | - Yang Wang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| |
Collapse
|
|
48
|
Lappano R, Mallet C, Rizzuti B, Grande F, Galli GR, Byrne C, Broutin I, Boudieu L, Eschalier A, Jacquot Y, Maggiolini M. The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells. Cells 2019; 8:cells8060590. [PMID: 31207943 PMCID: PMC6627388 DOI: 10.3390/cells8060590] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 06/13/2019] [Indexed: 12/18/2022] Open
Abstract
The inhibition of the G protein-coupled estrogen receptor (GPER) offers promising perspectives for the treatment of breast tumors. A peptide corresponding to part of the hinge region/AF2 domain of the human estrogen receptor α (ERα17p, residues 295–311) exerts anti-proliferative effects in various breast cancer cells including those used as triple negative breast cancer (TNBC) models. As preliminary investigations have evoked a role for the GPER in the mechanism of action of this peptide, we focused our studies on this protein using SkBr3 breast cancer cells, which are ideal for GPER evaluation. ERα17p inhibits cell growth by targeting membrane signaling. Identified as a GPER inverse agonist, it co-localizes with GPER and induces the proteasome-dependent downregulation of GPER. It also decreases the level of pEGFR (phosphorylation of epidermal growth factor receptor), pERK1/2 (phosphorylation of extracellular signal-regulated kinase), and c-fos. ERα17p is rapidly distributed in mice after intra-peritoneal injection and is found primarily in the mammary glands. The N-terminal PLMI motif, which presents analogies with the GPER antagonist PBX1, reproduces the effect of the whole ERα17p. Thus, this motif seems to direct the action of the entire peptide, as highlighted by docking and molecular dynamics studies. Consequently, the tetrapeptide PLMI, which can be claimed as the first peptidic GPER disruptor, could open new avenues for specific GPER modulators.
Collapse
Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
| | - Christophe Mallet
- NEURO-DOL Basics & Clinical Pharmacology of Pain, INSERM, CHU, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
- ANALGESIA Institute, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Bruno Rizzuti
- CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, 87036 Rende, Italy.
| | - Fedora Grande
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
| | - Giulia Raffaella Galli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
| | - Cillian Byrne
- Laboratoire des Biomolécules (LBM), CNRS-UMR 7203, Sorbonne University, Ecole Normale Supérieure, 75252 Paris Cedex 05, France.
| | - Isabelle Broutin
- Cibles Thérapeutiques et Conception de Médicaments (CiTCoM), CNRS-UMR 8038, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, 75270 Paris Cedex 06, France.
| | - Ludivine Boudieu
- NEURO-DOL Basics & Clinical Pharmacology of Pain, INSERM, CHU, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
- ANALGESIA Institute, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Alain Eschalier
- NEURO-DOL Basics & Clinical Pharmacology of Pain, INSERM, CHU, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
- ANALGESIA Institute, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Yves Jacquot
- Laboratoire des Biomolécules (LBM), CNRS-UMR 7203, Sorbonne University, Ecole Normale Supérieure, 75252 Paris Cedex 05, France.
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
| |
Collapse
|
|
49
|
Somani YB, Pawelczyk JA, De Souza MJ, Kris-Etherton PM, Proctor DN. Aging women and their endothelium: probing the relative role of estrogen on vasodilator function. Am J Physiol Heart Circ Physiol 2019; 317:H395-H404. [PMID: 31173499 DOI: 10.1152/ajpheart.00430.2018] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Despite significant decreases in cardiovascular disease (CVD) mortality in the past three decades, it still remains the leading cause of death in women. Following menopause and the accompanying loss of estrogen, women experience a unique, accelerated rise in CVD risk factors. Dysfunction of the endothelium represents an important antecedent to CVD development, with rapid declines in endothelial vasodilator function reportedly taking place across the menopause transition. Importantly, the decline in endothelial function is independent of chronological age and is associated with estrogen deficiency. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving endothelial health. This review will discuss studies that have probed the role of estrogen on endothelial vasodilator function in women at discrete stages of the menopause transition and the effects of estradiol supplementation in postmenopausal women. Estrogen receptor signaling is also an important aspect of endothelial function in women, and studies suggest that expression is reduced with both acute and prolonged estrogen deficiency. Changes in regulatory mechanisms of estrogen receptor-α expression as well as sensitivity to estrogen may underlie the differential effects of estrogen therapy in early (≤5 yr past final menstrual period) and late postmenopausal women (>5 yr past final menstrual period). Lastly, this review presents potential therapeutic targets that include increasing l-arginine bioavailability and estrogen receptor activation to prevent endothelial dysfunction in postmenopausal women as a strategy for decreasing CVD mortality in this high-risk population.
Collapse
Affiliation(s)
- Yasina B Somani
- Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania
| | - James A Pawelczyk
- Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania
| | - Mary Jane De Souza
- Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania
| | - Penny M Kris-Etherton
- Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania
| | - David N Proctor
- Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania
| |
Collapse
|
|
50
|
El-Abd E, Matta CA, Sheta M, El-Kerm Y, Sakr S. Histopathological characteristics of breast cancer and evaluation of ER alpha and Her-2neu using immunohistochemical and RT-PCR techniques. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2014.03.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Affiliation(s)
- Eman El-Abd
- Molecular Biology Department, Medical Technology Centre (MTC), Medical Research Institute (MRI), Alexandria University, Egypt
- Radiation Sciences Department, Medical Research Institute (MRI), Alexandria University, Egypt
| | - Cecil A. Matta
- Zoology Department, Faculty of Science, Alexandria University, Egypt
| | - Manal Sheta
- Pathology Department, Medical Research Institute (MRI), Alexandria University, Egypt
| | - Yasser El-Kerm
- Cancer Research and Management Department, Medical Research Institute (MRI), Alexandria University, Egypt
| | - Shimaa Sakr
- Medical Technology Centre (MTC), Medical Research Institute (MRI), Alexandria University, Egypt
| |
Collapse
|