DOCSLIB.ORG

GPER-Targeted, Tc-Labeled, Nonsteroidal Ligands Demonstrate

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
GPER-Targeted, Tc-Labeled, Nonsteroidal Ligands Demonstrate Published OnlineFirst July 16, 2014; DOI: 10.1158/1541-7786.MCR-14-0289 Molecular Cancer Oncogenes and Tumor Suppressors Research GPER-Targeted, 99mTc-Labeled, Nonsteroidal Ligands Demonstrate Selective Tumor Imaging and In Vivo Estrogen Binding Tapan K. Nayak1,2, Chinnasamy Ramesh3, Helen J. Hathaway1,4, Jeffrey P. Norenberg2,4, Jeffrey B. Arterburn3,4, and Eric R. Prossnitz1,4 Abstract Our understanding of estrogen (17b-estradiol, E2) receptor biology has evolved in recent years with the discovery and characterization of a 7-transmembrane-spanning G protein–coupled estrogen receptor (GPER/GPR30) and the development of GPER-selective functional chemical probes. GPER is highly expressed in certain breast, endometrial, and ovarian cancers, establishing the importance of noninvasive methods to evaluate GPER expression in vivo.Here, we developed 99mTc-labeled GPER ligands to demonstrate the in vivo status of GPER as an estrogen receptor (ER) and for GPER visualization in whole animals. A series of 99mTc(I)-labeled nonsteroidal tetrahydro-3H-cyclopen- ta[c]quinolone derivatives was synthesized utilizing pyridin-2-yl hydrazine and picolylamine chelates. Radioligand receptor binding studies revealed binding affinities in the 10 to 30 nmol/L range. Cell signaling assays previously demonstrated that derivatives retaining a ketone functionality displayed agonist properties, whereas those lacking such a hydrogen bond acceptor were antagonists. In vivo biodistribution and imaging studies performed on mice bearing human endometrial and breast cancer cell xenografts yielded significant tumor uptake (0.4–1.1%ID/g). Blocking studies revealed specific uptake in multiple organs (adrenals, uterus, and mammary tissue), as well as tumor uptake with similar levels of competition by E2 and G-1, a GPER-selective agonist. In conclusion, we synthesized and evaluated a series of first-generation 99mTc-labeled GPER-specific radioligands, demonstrating GPER as an estrogen- binding receptor for the first time in vivo using competitive binding principles, and establishing the utility of such ligands as tumor imaging agents. These results warrant further investigation into the role of GPER in estrogen- mediated carcinogenesis and as a target for diagnostic/therapeutic/image-guided drug delivery. Implications: These studies provide a molecular basis to evaluate GPER expression and function as an ER through in vivo imaging. Mol Cancer Res; 12(11); 1635–43. Ó2014 AACR. Introduction in premenopausal women compared with postmenopausal Estrogens mediate profound effects throughout the body women or age-matched men is widely attributed to the presence of 17b-estradiol (E2), the predominant and most and regulate physiologic and pathologic processes in both – women and men. The lower prevalence of many diseases potent endogenous estrogen (1 3). E2, although common- ly recognized as the female sex hormone, also has critical roles in additional normal physiologic processes within the nervous, immune, vascular, muscular, skeletal, and endo- 1Department of Cell Biology and Physiology, School of Medicine, Univer- – sity of New Mexico Health Science Center, Albuquerque, New Mexico. crine systems (2, 4 8). In addition, E2 signaling plays an 2College of Pharmacy, University of New Mexico Health Science Center, important role in various pathologic conditions and dis- Albuquerque, New Mexico. 3Department of Chemistry and Biochemistry, orders, including cancer, cardiovascular diseases, hyperten- New Mexico State University, Las Cruces, New Mexico. 4University of New Mexico Cancer Center, University of New Mexico Health Science Center, sion, osteoporosis, cognitive and behavioral alterations, Albuquerque, New Mexico. neurodegenerative diseases, as well as metabolic and im- – Note: Supplementary data for this article are available at Molecular Cancer mune disorders (2, 4 8). However, elucidating the exact Research Online (http://mcr.aacrjournals.org/). role(s) of E2 in these processes is often complicated by the Current address for T.K. Nayak: F Hoffmann-La Roche AG, Grenzacher- existence of several types of E2 receptors (ERs) and mul- strasse 124, 4070 Basel, Switzerland. tiple modes of cellular signaling mechanisms that span time Corresponding Author: Eric R. Prossnitz, Department of Cell Biology and frames from seconds to hours, or even days (6, 9). The Physiology, University of New Mexico, Albuquerque, NM 87131. Phone: actions of E2 have traditionally been ascribed to one of the 505-272-5647; Fax: 505-272-1421; E-mail: [email protected] two closely related classical nuclear hormone receptors, doi: 10.1158/1541-7786.MCR-14-0289 ERa and ERb, which are best characterized for regulating Ó2014 American Association for Cancer Research. gene expression (10, 11), and their membrane-localized www.aacrjournals.org 1635 Downloaded from mcr.aacrjournals.org on September 30, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst July 16, 2014; DOI: 10.1158/1541-7786.MCR-14-0289 Nayak et al. variants. Recent studies have revealed the contribution of tive 99mTc-labeled agents for demonstrating the status of a novel G protein-coupled estrogen receptor GPER (pre- GPER as an ER in vitro and in vivo. In vivo biodistribution viously GPR30), which belongs to the family of seven- and competition binding studies with E2 and G-1 were transmembrane G protein–coupled receptors, to many of performed in mice bearing ERa/b-negative and GPER- the rapid cellular and biologic responses to E2 (6, 12–14). expressing type II human endometrial carcinoma Hec50 GPER is expressed in numerous tissues and the scope of tumors and ERa/b- and GPER-positive human breast research into its many functions has increased dramatically adenocarcinoma MCF7/HER2-18 tumors. Our results over the last decade (15–23); nevertheless, isolated reports demonstrate not only that GPER functions in vivo as have failed to observe GPER-mediated estrogenic responses an E2-binding receptor, but also that GPER-selective in the uterus or the mammary gland or GPER-dependent 99mTc-labeled ligands can be used to visualize breast and estrogen binding in cell-based systems (24–26). endometrial tumors in vivo. GPER protein is (over) expressed in approximately 50% of all breast cancers and correlates with clinical and patho- logic biomarkers of poor outcome, such as tumor size and the Materials and Methods presence of metastases, regardless of ER status (27). Addi- Chemical synthesis of nonsteroidal GPER-specific tional studies have found that GPER protein is overexpressed ligands in ovarian cancer where it is associated with lower survival Synthetic derivatives of the GPER-targeting tetrahydro- rates (28, 29). Similarly, GPER is overexpressed in tumors 3H-cyclopenta[c]quinoline scaffold possessing different che- where E2 and progesterone receptors are downregulated and lating heterocyclic aminocarboxylate ligands with demon- in high-risk endometrial cancer patients with lower survival strated capacity for the formation of neutral tricarbonylrhe- rates (30, 31). GPER is also widely expressed in cancer cell nium(I) and tricarbonyltechnetium(I) complexes at the C8 lines isolated from diverse organs as well as primary tumors of position were prepared as previously described (54). Ligand the thyroid, lung, prostate, pancreas, and testicular germ compounds containing a pyridin-2-yl-hydrazinylethanoic cells, in addition to the breast, endometrium, and ovaries acid group (1,3,4), or pyridin-2-yl-methylaminoethanoic (6, 12, 32–34). acid (2), were prepared as the tert-butyl esters with nitrogen Importantly, in patients with breast cancer treated only groups protected as tert-butoxycarbonyl derivatives, and with tamoxifen, GPER protein expression increased and deprotected with trifluoroacetic acid in dichloromethane at survival was markedly reduced in patients with initial GPER- ambient temperature before labeling. The nonradioactive positive tumors, suggesting that patients with breast cancer tricarbonylrhenium(I) complexes (5-Re - 8-Re) were pre- who have high GPER protein expression should not be pared as previously described (54). treated exclusively with tamoxifen (35). Cellular effects of tamoxifen via GPER were further demonstrated through Radiosynthesis of 99mTc(I)-labeled nonsteroidal tamoxifen-mediated stimulation of tumor cell proliferation GPER-specific ligands and migration (36–38). Thus, although anti-estrogens such The organometallic aqua ion labeling agent [99mTc a þ as tamoxifen, fulvestrant, and raloxifene function as ER (CO)3(H2O)3] was prepared by adding 3.7 GBq of freshly – 99m antagonists, they act as GPER agonists (39 42), stimulating eluted Na- TcO4 to the Isolink kit (Tyco healthcare, proliferation and other cellular activities via the GPER- Mallinckrodt) as previously described (55). The alkaline 99m þ mediated transactivation of EGFR (43). [ Tc(CO)3(H2O)3] mixture was then neutralized to Several radiopharmaceuticals have been developed pH 7 with acetic acid. The synthetic chelates 1-4 were for the noninvasive imaging and assessment of ER status dissolved in ethanol and 10 mg of each derivative was added – a 99m þ (44 48). The most successful E2 radiopharmaceutical 16 - to the prepared [ Tc(CO)3(H2O)3] mixture. The reac- [18F]fluoroestradiol-17b (FES) is under clinical investiga- tion mixture was stirred for 2 hours at room temperature. tion and to date has produced promising results in PET Alternatively, the mixture was heated to 80C for 30 imaging of ER-expressing tumors, in particular for the evalua- minutes
Load more

Recommended publications
  • Targeting Lysophosphatidic Acid in Cancer: the Issues in Moving from Bench to Bedside
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by IUPUIScholarWorks cancers Review Targeting Lysophosphatidic Acid in Cancer: The Issues in Moving from Bench to Bedside Yan Xu Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut Street R2-E380, Indianapolis, IN 46202, USA; [email protected]; Tel.: +1-317-274-3972 Received: 28 August 2019; Accepted: 8 October 2019; Published: 10 October 2019 Abstract: Since the clear demonstration of lysophosphatidic acid (LPA)’s pathological roles in cancer in the mid-1990s, more than 1000 papers relating LPA to various types of cancer were published. Through these studies, LPA was established as a target for cancer. Although LPA-related inhibitors entered clinical trials for fibrosis, the concept of targeting LPA is yet to be moved to clinical cancer treatment. The major challenges that we are facing in moving LPA application from bench to bedside include the intrinsic and complicated metabolic, functional, and signaling properties of LPA, as well as technical issues, which are discussed in this review. Potential strategies and perspectives to improve the translational progress are suggested. Despite these challenges, we are optimistic that LPA blockage, particularly in combination with other agents, is on the horizon to be incorporated into clinical applications. Keywords: Autotaxin (ATX); ovarian cancer (OC); cancer stem cell (CSC); electrospray ionization tandem mass spectrometry (ESI-MS/MS); G-protein coupled receptor (GPCR); lipid phosphate phosphatase enzymes (LPPs); lysophosphatidic acid (LPA); phospholipase A2 enzymes (PLA2s); nuclear receptor peroxisome proliferator-activated receptor (PPAR); sphingosine-1 phosphate (S1P) 1.
    [Show full text]
  • Glucocorticoid Regulation of the G-Protein Coupled Estrogen Receptor (GPER) in Mouse Hippocampal Neurons
    Glucocorticoid Regulation of the G-Protein Coupled Estrogen Receptor (GPER) in Mouse Hippocampal Neurons by Kate Colleen Eliza Nicholson A Thesis presented to The University of Guelph In partial fulfilment of requirements for the degree of Master of Science in Biomedical Sciences Guelph, Ontario, Canada © Kate Colleen Eliza Nicholson, August, 2019 ABSTRACT GLUCOCORTICOID REGULATION OF THE G-PROTEIN COUPLED ESTROGEN RECEPTOR (GPER) IN MOUSE HIPPOCAMPAL NEURONS Kate Colleen Eliza Nicholson Advisor: University of Guelph, 2019 Dr. Neil J. MacLusky The most prevalent estrogen, 17β-estradiol, binds the non-classical G-protein coupled estrogen receptor (GPER) with high affinity resulting in rapid activation of the c- jun N terminal kinase (JNK) pathway. GPER activation mediates some of the rapid neurotrophic and memory-enhancing effects of 17β-estradiol in the female hippocampus. However, exposure to stressful stimuli may impair these beneficial effects. This thesis characterizes neurosteroid receptor expression in murine-derived mHippoE cell lines that are subsequently used to investigate the glucocorticoid regulation of GPER protein expression and functional activation. This thesis demonstrates that 24-hour treatment with a glucocorticoid receptor agonist reduces GPER protein expression and activation of JNK in female-derived mHippoE-14s. Using an in vivo model, treatment with glucocorticoids significantly reduces hippocampal activation of JNK in female ovariectomized CD1 mice. Collectively, this thesis uses in vitro and in vivo models to characterize glucocorticoid regulation of GPER expression and signalling in female murine hippocampal neurons. ACKNOWLEDGEMENTS To Dr. MacLusky: I would like to thank you for inspiring my passion for science and pursuit of knowledge. Over the past 2 years, you have provided me with countless opportunities to grow as a young researcher and I am tremendously grateful for this.
    [Show full text]
  • G Protein-Coupled Estrogen Receptor Inhibits the P2Y Receptor-Mediated Ca2+ Signaling Pathway in Human Airway Epithelia
    Pflugers Arch - Eur J Physiol DOI 10.1007/s00424-016-1840-7 SIGNALING AND CELL PHYSIOLOGY G protein-coupled estrogen receptor inhibits the P2Y receptor-mediated Ca2+ signaling pathway in human airway epithelia Yuan Hao1 & Alison W. Chow1 & Wallace C. Yip 1 & Chi H. Li1 & Tai F. Wan 1 & Benjamin C. Tong2 & King H. Cheung2 & Wood Y. Chan 1 & Yangchao Chen 1 & Christopher H. Cheng1 & Wing H. Ko1 Received: 21 January 2016 /Revised: 11 May 2016 /Accepted: 22 May 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract P2Y receptor activation causes the release of in- inhibitory effects of G1 or E2 on P2Y receptor-mediated flammatory cytokines in the bronchial epithelium, whereas Ca2+ mobilization and cytokine secretion were due to G protein-coupled estrogen receptor (GPER), a novel estrogen GPER-mediated activation of a cAMP-dependent PKA path- (E2) receptor, may play an anti-inflammatory role in this pro- way. This study has reported, for the first time, the expression cess. We investigated the cellular mechanisms underlying the and function of GPER as an anti-inflammatory component in inhibitory effect of GPER activation on the P2Y receptor- human bronchial epithelia, which may mediate through its mediated Ca2+ signaling pathway and cytokine production in opposing effects on the pro‐inflammatory pathway activated airway epithelia. Expression of GPER in primary human by the P2Y receptors in inflamed airway epithelia. bronchial epithelial (HBE) or 16HBE14o- cells was con- firmed on both the mRNA and protein levels. Stimulation of Keywords GPER . P2Y receptor signaling pathway . Human HBE or 16HBE14o- cells with E2 or G1, a specific agonist of .
    [Show full text]
  • G Protein-Coupled Receptors Function As Cell Membrane Receptors for the Steroid Hormone 20-Hydroxyecdysone Xiao-Fan Zhao
    Zhao Cell Communication and Signaling (2020) 18:146 https://doi.org/10.1186/s12964-020-00620-y REVIEW Open Access G protein-coupled receptors function as cell membrane receptors for the steroid hormone 20-hydroxyecdysone Xiao-Fan Zhao Abstract G protein-coupled receptors (GPCRs) are cell membrane receptors for various ligands. Recent studies have suggested that GPCRs transmit animal steroid hormone signals. Certain GPCRs have been shown to bind steroid hormones, for example, G protein-coupled estrogen receptor 1 (GPER1) binds estrogen in humans, and Drosophila dopamine/ecdysteroid receptor (DopEcR) binds the molting hormone 20-hydroxyecdysone (20E) in insects. This review summarizes the research progress on GPCRs as animal steroid hormone cell membrane receptors, including the nuclear and cell membrane receptors of steroid hormones in mammals and insects, the 20E signaling cascade via GPCRs, termination of 20E signaling, and the relationship between genomic action and the nongenomic action of 20E. Studies indicate that 20E induces a signal via GPCRs to regulate rapid cellular responses, including rapid Ca2+ release from the endoplasmic reticulum and influx from the extracellular medium, as well as rapid protein phosphorylation and subcellular translocation. 20E via the GPCR/Ca2+/PKC/signaling axis and the GPCR/cAMP/PKA- signaling axis regulates gene transcription by adjusting transcription complex formation and DNA binding activity. GPCRs can bind 20E in the cell membrane and after being isolated, suggesting GPCRs as cell membrane receptors of 20E. This review deepens our understanding of GPCRs as steroid hormone cell membrane receptors and the GPCR-mediated signaling pathway of 20E (20E-GPCR pathway), which will promote further study of steroid hormone signaling via GPCRs, and presents GPCRs as targets to explore new pharmaceutical materials to treat steroid hormone-related diseases or control pest insects.
    [Show full text]
  • Download (PDF)
    Supplemental Information Biological and Pharmaceutical Bulletin Promoter Methylation Profiles between Human Lung Adenocarcinoma Multidrug Resistant A549/Cisplatin (A549/DDP) Cells and Its Progenitor A549 Cells Ruiling Guo, Guoming Wu, Haidong Li, Pin Qian, Juan Han, Feng Pan, Wenbi Li, Jin Li, and Fuyun Ji © 2013 The Pharmaceutical Society of Japan Table S1. Gene categories involved in biological functions with hypomethylated promoter identified by MeDIP-ChIP analysis in lung adenocarcinoma MDR A549/DDP cells compared with its progenitor A549 cells Different biological Genes functions transcription factor MYOD1, CDX2, HMX1, THRB, ARNT2, ZNF639, HOXD13, RORA, FOXO3, HOXD10, CITED1, GATA1, activity HOXC6, ZGPAT, HOXC8, ATOH1, FLI1, GATA5, HOXC4, HOXC5, PHTF1, RARB, MYST2, RARG, SIX3, FOXN1, ZHX3, HMG20A, SIX4, NR0B1, SIX6, TRERF1, DDIT3, ASCL1, MSX1, HIF1A, BAZ1B, MLLT10, FOXG1, DPRX, SHOX, ST18, CCRN4L, TFE3, ZNF131, SOX5, TFEB, MYEF2, VENTX, MYBL2, SOX8, ARNT, VDR, DBX2, FOXQ1, MEIS3, HOXA6, LHX2, NKX2-1, TFDP3, LHX6, EWSR1, KLF5, SMAD7, MAFB, SMAD5, NEUROG1, NR4A1, NEUROG3, GSC2, EN2, ESX1, SMAD1, KLF15, ZSCAN1, VAV1, GAS7, USF2, MSL3, SHOX2, DLX2, ZNF215, HOXB2, LASS3, HOXB5, ETS2, LASS2, DLX5, TCF12, BACH2, ZNF18, TBX21, E2F8, PRRX1, ZNF154, CTCF, PAX3, PRRX2, CBFA2T2, FEV, FOS, BARX1, PCGF2, SOX15, NFIL3, RBPJL, FOSL1, ALX1, EGR3, SOX14, FOXJ1, ZNF92, OTX1, ESR1, ZNF142, FOSB, MIXL1, PURA, ZFP37, ZBTB25, ZNF135, HOXC13, KCNH8, ZNF483, IRX4, ZNF367, NFIX, NFYB, ZBTB16, TCF7L1, HIC1, TSC22D1, TSC22D2, REXO4, POU3F2, MYOG, NFATC2, ENO1,
    [Show full text]
  • Sex Steroids Regulate Skin Pigmentation Through Nonclassical
    RESEARCH ARTICLE Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors Christopher A Natale1, Elizabeth K Duperret1, Junqian Zhang1, Rochelle Sadeghi1, Ankit Dahal1, Kevin Tyler O’Brien2, Rosa Cookson2, Jeffrey D Winkler2, Todd W Ridky1* 1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 2Department of Chemistry, University of Pennsylvania, Philadelphia, United States Abstract The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17b-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics. DOI: 10.7554/eLife.15104.001 *For correspondence: ridky@mail.
    [Show full text]
  • I GPER/GPR30 ESTROGEN RECEPTOR
    GPER/GPR30 ESTROGEN RECEPTOR: A TARGET FOR PAIN MODULATION A Dissertation Submitted to The Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy By Elena Deliu May, 2012 Examination Committee Members: Dr. Nae J Dun (Advisor), Dept. of Pharmacology, Temple University Dr. Mary E Abood, Dept. of Anatomy and Cell Biology, Temple University Dr. Barrie Ashby, Dept. of Pharmacology, Temple University Dr. Eugen Brailoiu, Dept. of Pharmacology, Temple University Dr. Ellen M Unterwald, Dept. of Pharmacology, Temple University Dr. Hreday Sapru, (External Examiner), Depts. of Neurosciences, Neurosurgery & Pharmacology/Physiology, UMDNJ-NJMS i © 2012 By Elena Deliu All Rights Reserved ii ABSTRACT GPER/GPR30 ESTROGEN RECEPTOR: A TARGET FOR PAIN MODULATION Elena Deliu Doctor of Philosophy Temple University, 2012 Doctoral Advisory Committee Chair: Nae J. Dun, Ph.D. The G protein-coupled estrogen receptor GPER/GPER1, also known as GPR30, was originally cloned as an orphan receptor and later shown to be specifically activated by 17- β-estradiol. This has led to its classification as an estrogen receptor and expanded the perspective on the mechanisms underlying the rapid estrogenic effects reported over the years. GPER is strongly expressed in the central nervous system and peripheral tissues and appears to be involved in a wide variety of physiological and pathological processes. Estrogens are known to alter the processing of nociceptive sensory information and analgesic responses in the central nervous system. Both analgesic and pro-nociceptive effects of estrogens have been reported. Some pro-algesic estrogenic responses have a short latency, suggesting a non-genomic mechanism of action.
    [Show full text]
  • Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: a Comparison by Computational Prediction
    molecules Article Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction Giulia D’Arrigo 1, Eleonora Gianquinto 1, Giulia Rossetti 2,3,4 , Gabriele Cruciani 5, Stefano Lorenzetti 6,* and Francesca Spyrakis 1,* 1 Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy; [email protected] (G.D.); [email protected] (E.G.) 2 Institute for Neuroscience and Medicine (INM-9) and Institute for Advanced Simulations (IAS-5) “Computational Biomedicine”, Forschungszentrum Jülich, 52425 Jülich, Germany 3 Jülich Supercomputing Center (JSC), Forschungszentrum Jülich, 52425 Jülich, Germany 4 Department of Neurology, RWTH, Aachen University, 52074 Aachen, Germany; [email protected] 5 Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy; [email protected] 6 Istituto Superiore di Sanità (ISS), Department of Food Safety, Nutrition and Veterinary Public Health, Viale Regina Elena 299, 00161 Rome, Italy * Correspondence: [email protected] (S.L.); [email protected] (F.S.) Abstract: Flavonoids are plant bioactives that are recognized as hormone-like polyphenols because of Citation: D’Arrigo, G.; Gianquinto, their similarity to the endogenous sex steroids 17β-estradiol and testosterone, and to their estrogen- E.; Rossetti, G.; Cruciani, G.; and androgen-like activity. Most efforts to verify flavonoid binding to nuclear receptors (NRs) and Lorenzetti, S.; Spyrakis, F. Binding of explain their action have been focused on ERα, while less attention has been paid to other nuclear Androgen- and Estrogen-Like and non-nuclear membrane androgen and estrogen receptors. Here, we investigate six flavonoids Flavonoids to Their Cognate (apigenin, genistein, luteolin, naringenin, quercetin, and resveratrol) that are widely present in fruits (Non)Nuclear Receptors: A and vegetables, and often used as replacement therapy in menopause.
    [Show full text]
  • Maternal Testosterone Exposure Increases Anxiety-Like Behavior and Impacts the Limbic System in the Offspring
    Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring Min Hua,b,1, Jennifer Elise Richardc,1, Manuel Maliqueoa,d,1, Milana Kokosarc, Romina Fornesa, Anna Benrickc, Thomas Janssone, Claes Ohlssonf, Xiaoke Wub,2, Karolina Patrycja Skibickac,3, and Elisabet Stener-Victorina,2,3 aDepartment of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; bDepartment of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China; cDepartment of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; dEndocrinology and Metabolism Laboratory, Department of Medicine West Division, School of Medicine, University of Chile, 8320000 Santiago, Chile; eDepartment of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; and fCentre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved October 1, 2015 (received for review April 30, 2015) During pregnancy, women with polycystic ovary syndrome (PCOS) Maternal testosterone levels in humans have been shown to af- display high circulating androgen levels that may affect the fetus fect brain morphology and function (6) and to be correlated to and increase the risk of mood disorders in offspring. This study neural development and mental function (7). There is evidence for investigated whether maternal androgen excess causes anxiety-like a crucial role of the hippocampus and the amygdala in the devel- behavior in offspring mimicking anxiety disorders in PCOS.
    [Show full text]
  • G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives
    cells Review G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives Richard A. Pepermans 1, Geetanjali Sharma 1,2 and Eric R. Prossnitz 1,2,3,* 1 Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; [email protected] (R.A.P.); [email protected] (G.S.) 2 Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA 3 University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA * Correspondence: [email protected]; Tel.: +1-505-272-5647 Abstract: Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1.
    [Show full text]
  • Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.21.053348; this version posted April 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Membrane estrogen receptor (GPER) and follicle-stimulating hormone receptor heteromeric complexes promote human ovarian follicle survival One Sentence Summary: FSHR/GPER heteromers block cAMP-dependent selection of ovarian follicles and target tumor growth and poor FSH-response in women. Authors: Livio Casarini1,2,*, Clara Lazzaretti1,3, Elia Paradiso1,3, Silvia Limoncella1, Laura Riccetti1, Samantha Sperduti1,2, Beatrice Melli1, Serena Marcozzi4, Claudia Anzivino1, Niamh S. Sayers5, Jakub Czapinski6, 7, Giulia Brigante1,8, Francesco Potì9, Antonio La Marca10,11, Francesco De Pascali12, Eric Reiter12, Angela Falbo13, Jessica Daolio13, Maria Teresa Villani13, Monica Lispi14, Giovanna Orlando15, Francesca G. Klinger4, Francesca Fanelli16,17, Adolfo Rivero-Müller6, Aylin C. Hanyaloglu5, Manuela Simoni1,2,8,12 Affiliations: 1Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy 2Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy 3International PhD School in Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, Modena, Italy 4Histology and Embryology Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy bioRxiv preprint doi: https://doi.org/10.1101/2020.04.21.053348; this version posted April 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
    [Show full text]
  • Br J Pharmacol
    Supplementary Information Supplementary Table 1. List of polypeptide cell surface receptor and their cognate ligand genes. Supplementary Table 2. List of coding SNPs with high FST ( > 0.5) in human GPCR and their cognate ligand genes. Supplementary Table 3. List of coding SNPs with high FST ( > 0.5) in human nonGPCR receptor and ligand genes. Supplementary Table 4. List of genotyped SNPs from 44246961 to 44542055 on chromosome 17. The HapMap II dataset was analyzed using HaploView. The 101 SNPs included in LD plots of Supplementary Fig. 3 (A-C) are highlighted by a grey background. The 37 SNPs used in the haplotype analysis of Fig. 2C are indicated by red letters. SNPs that are linked with rs2291725 are indicated by bold red letters. Supplementary Table 5. Allele frequency of rs2291725 in the HGDP-CEPH populations. Frequencies of GIP103T and GIP103C alleles in each of the 52 populations from the seven geographical regions and the number of chromosomes analyzed for each population. 1 Supplementary Table 6. EC50 values for GIP receptor activation at four different time points after incubation with pooled human serum or pooled complement-preserved human serum (N=4). Supplementary Table 7. EC50 values for GIP receptor activation at three different time points after incubation with a recombinant DPP IV enzyme (N=4). Supplementary Fig. 1. Cumulative distribution function (CDF) plots for the FST of coding SNPs in human GPCRs and their cognate ligand genes (blue) and all other human genes (magenta). The FST was computed between three HapMap II populations (CEU, YRI, and ASN), and coding SNPs have been split into synonymous and nonsynonymous groups.
    [Show full text]