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Role of the G Protein-Coupled Receptors in Cancer and Stromal...
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Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 47242

Special Issue Editor

Prof. Dr. Marcello Maggiolini

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Guest Editor
Full Professor, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Cosenza, Italy
Interests: estrogen; estrogen receptor; GPER; signal transduction; breast cancer; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Heterotrimeric G proteins consist of four subfamilies (Gs, Gi/o, Gq/11, and G12/13) involved in a multifaceted signalling network through the G-protein coupled receptors (GPCRs) that belong to the largest gene family of cell-surface receptors. Considering that many GPCRs play a key role in numerous physiological functions, their involvement in various human diseases, including cancer, is not surprising. In this regard, emerging evidence strongly suggests that GPCRs may drive certain aberrant features that characterize the tumorigenic processes, such as cell proliferation, survival, invasion, metastasis, angiogenesis, immune evasion, and therapy resistance. To date, GPCRs represent the therapeutic targets of more than a quarter of the clinical drugs currently on the market. A deeper assessment of their action in cancer development may provide a further fascinating chance toward the identification of novel targets to be exploited in drug discovery and tumor treatment in line with the new era of precision medicine.

We invite scientists working on this topic to contribute to this Special Issue. Original research articles or reviews on all aspects related to the molecular and cellular mechanisms through which GPCRs trigger not only cancer cells but also the malignant liaison within the tumor microenvironment are welcome. Articles with insights from biological to therapeutic perspectives are especially welcome.

Prof. Marcello Maggiolini
Guest Editor

Manuscript Submission Information

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Keywords

  • G proteins
  • GPCRs
  • cancer
  • tumor microenvironment
  • therapeutic perspectives

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Related Special Issue

Published Papers (9 papers)

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Research

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16 pages, 2403 KiB  
Article
A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells
by Marzia Di Donato, Pia Giovannelli, Maria Vittoria Barone, Ferdinando Auricchio, Gabriella Castoria and Antimo Migliaccio
Cells 2022, 11(1), 14; https://doi.org/10.3390/cells11010014 - 22 Dec 2021
Cited by 11 | Viewed by 3775
Abstract
Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. [...] Read more.
Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. We report here that the AR associates with Filamin A (FlnA) promoting migration and invasiveness of various PC-derived cells after androgen challenging. Inhibition of the AR/FlnA complex assembly by a very low concentration of Rh-2025u, an AR-derived peptide specifically interfering with this association, impairs such phenotype in monolayer cells and in 3D models. This study, together with our recent data in cancer-associated fibroblasts (CAFs), indicates that targeting the AR/FlnA complex could improve the clinical management of invasive PC, as the limited number of new drugs reaching the market suggests that we must re-examine the way invasive PC is currently treated. In this context, the synthesis of new biologically active molecules, such as the Rh-2025u peptide, which has been shown to efficiently interfere in the complex assembly in CAFs and PC cells, should overcome the limits of current available therapies, mostly based on hormone antagonists. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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13 pages, 990 KiB  
Article
The G Protein-Coupled Estrogen Receptor (GPER) Expression Correlates with Pro-Metastatic Pathways in ER-Negative Breast Cancer: A Bioinformatics Analysis
by Marianna Talia, Ernestina Marianna De Francesco, Damiano Cosimo Rigiracciolo, Maria Grazia Muoio, Lucia Muglia, Antonino Belfiore, Marcello Maggiolini, Andrew H. Sims and Rosamaria Lappano
Cells 2020, 9(3), 622; https://doi.org/10.3390/cells9030622 - 4 Mar 2020
Cited by 34 | Viewed by 4507
Abstract
The G protein-coupled estrogen receptor (GPER, formerly known as GPR30) is a seven-transmembrane receptor that mediates estrogen signals in both normal and malignant cells. In particular, GPER has been involved in the activation of diverse signaling pathways toward transcriptional and biological responses that [...] Read more.
The G protein-coupled estrogen receptor (GPER, formerly known as GPR30) is a seven-transmembrane receptor that mediates estrogen signals in both normal and malignant cells. In particular, GPER has been involved in the activation of diverse signaling pathways toward transcriptional and biological responses that characterize the progression of breast cancer (BC). In this context, a correlation between GPER expression and worse clinical-pathological features of BC has been suggested, although controversial data have also been reported. In order to better assess the biological significance of GPER in the aggressive estrogen receptor (ER)-negative BC, we performed a bioinformatics analysis using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation and the statistical analysis were carried out with R studio base functions and the tidyverse package. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on the Database for Annotation, Visualization and Integrated Discovery (DAVID) website, whereas gene set enrichment analysis (GSEA) was performed with the R package phenoTest. The survival analysis was determined with the R package survivALL. Analyzing the expression data of more than 2500 primary BC, we ascertained that GPER levels are associated with pro-migratory and metastatic genes belonging to cell adhesion molecules (CAMs), extracellular matrix (ECM)-receptor interaction, and focal adhesion (FA) signaling pathways. Thereafter, evaluating the disease-free interval (DFI) in ER-negative BC patients, we found that the subjects expressing high GPER levels exhibited a shorter DFI in respect to those exhibiting low GPER levels. Overall, our results may pave the way to further dissect the network triggered by GPER in the breast malignancies lacking ER toward a better assessment of its prognostic significance and the action elicited in mediating the aggressive features of the aforementioned BC subtype. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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16 pages, 7967 KiB  
Article
Interaction of the Anti-Proliferative GPER Inverse Agonist ERα17p with the Breast Cancer Cell Plasma Membrane: From Biophysics to Biology
by Michaël Trichet, Rosamaria Lappano, Mathilde Belnou, Lilian Shadai Salazar Vazquez, Isabel Alves, Delphine Ravault, Sandrine Sagan, Lucie Khemtemourian, Marcello Maggiolini and Yves Jacquot
Cells 2020, 9(2), 447; https://doi.org/10.3390/cells9020447 - 15 Feb 2020
Cited by 8 | Viewed by 3034
Abstract
The peptide ERα17p, which corresponds to the 295-311 fragment of the hinge/AF2 domains of the human estrogen receptor α (ERα), exerts apoptosis in breast cancer cells through a mechanism involving the G protein-coupled estrogen-dependent receptor GPER. Besides this receptor-mediated mechanism, we have detected [...] Read more.
The peptide ERα17p, which corresponds to the 295-311 fragment of the hinge/AF2 domains of the human estrogen receptor α (ERα), exerts apoptosis in breast cancer cells through a mechanism involving the G protein-coupled estrogen-dependent receptor GPER. Besides this receptor-mediated mechanism, we have detected a direct interaction (Kd value in the micromolar range) of this peptide with lipid vesicles mimicking the plasma membrane of eukaryotes. The reversible and not reversible pools of interacting peptide may correspond to soluble and aggregated membrane-interacting peptide populations, respectively. By using circular dichroism (CD) spectroscopy, we have shown that the interaction of the peptide with this membrane model was associated with its folding into β sheet. A slight leakage of the 5(6)-fluorescein was also observed, indicating lipid bilayer permeability. When the peptide was incubated with living breast cancer cells at the active concentration of 10 μM, aggregates were detected at the plasma membrane under the form of spheres. This insoluble pool of peptide, which seems to result from a fibrillation process, is internalized in micrometric vacuoles under the form of fibrils, without evidence of cytotoxicity, at least at the microscopic level. This study provides new information on the interaction of ERα17p with breast cancer cell membranes as well as on its mechanism of action, with respect to direct membrane effects. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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19 pages, 4382 KiB  
Article
Trifolium Repens Blocks Proliferation in Chronic Myelogenous Leukemia via the BCR-ABL/STAT5 Pathway
by Federica Sarno, Giacomo Pepe, Pasquale Termolino, Vincenzo Carafa, Crescenzo Massaro, Fabrizio Merciai, Pietro Campiglia, Angela Nebbioso and Lucia Altucci
Cells 2020, 9(2), 379; https://doi.org/10.3390/cells9020379 - 6 Feb 2020
Cited by 17 | Viewed by 3893
Abstract
Some species of clover are reported to have beneficial effects in human diseases. However, little is known about the activity of the forage plant Trifolium repens, or white clover, which has been recently found to exert a hepatoprotective action. Scientific interest is [...] Read more.
Some species of clover are reported to have beneficial effects in human diseases. However, little is known about the activity of the forage plant Trifolium repens, or white clover, which has been recently found to exert a hepatoprotective action. Scientific interest is increasingly focused on identifying new drugs, especially natural products and their derivatives, to treat human diseases including cancer. We analyzed the anticancer effects of T. repens in several cancer cell lines. The phytochemical components of T. repens were first extracted in a methanol solution and then separated into four fractions by ultra-high-performance liquid chromatography. The effects of the total extract and each fraction on cancer cell proliferation were analyzed by MTT assay and Western blotting. T. repens and, more robustly, its isoflavonoid-rich fraction showed high cytotoxic effects in chronic myelogenous leukemia (CML) K562 cells, with IC50 values of 1.67 and 0.092 mg/mL, respectively. The block of cell growth was associated with a total inhibition of BCR-ABL/STAT5 and activation of the p38 signaling pathways. In contrast, these strongly cytotoxic effects did not occur in normal cells. Our findings suggest that the development of novel compounds derived from phytochemical molecules contained in Trifolium might lead to the identification of new therapeutic agents active against CML. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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Review

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16 pages, 684 KiB  
Review
G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives
by Richard A. Pepermans, Geetanjali Sharma and Eric R. Prossnitz
Cells 2021, 10(3), 672; https://doi.org/10.3390/cells10030672 - 17 Mar 2021
Cited by 38 | Viewed by 4596
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 [...] Read more.
Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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38 pages, 486 KiB  
Review
Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?
by Jesús Cosín-Roger, Dolores Ortiz-Masia, Maria Dolores Barrachina and Sara Calatayud
Cells 2020, 9(11), 2345; https://doi.org/10.3390/cells9112345 - 23 Oct 2020
Cited by 22 | Viewed by 5290
Abstract
G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated [...] Read more.
G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated by metabolites. These metabolite sensing GPCRs control crucial processes, such as cell proliferation, differentiation, migration, and survival after their activation. In the present review, we will describe the main functions of these metabolite sensing GPCRs and shed light on the benefits of their potential use as possible pharmacological targets for cancer treatment. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
19 pages, 1220 KiB  
Review
Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis
by Adele Chimento, Arianna De Luca, Marta Claudia Nocito, Paola Avena, Davide La Padula, Lucia Zavaglia and Vincenzo Pezzi
Cells 2020, 9(9), 2115; https://doi.org/10.3390/cells9092115 - 17 Sep 2020
Cited by 33 | Viewed by 4940
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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17 pages, 1715 KiB  
Review
The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells
by Yu-De Chu and Chau-Ting Yeh
Cells 2020, 9(7), 1730; https://doi.org/10.3390/cells9071730 - 20 Jul 2020
Cited by 36 | Viewed by 9471
Abstract
The thyroid stimulating hormone (TSH) and its cognate receptor (TSHR) are of crucial importance for thyrocytes to proliferate and exert their functions. Although TSHR is predominantly expressed in thyrocytes, several studies have revealed that functional TSHR can also be detected in many extra-thyroid [...] Read more.
The thyroid stimulating hormone (TSH) and its cognate receptor (TSHR) are of crucial importance for thyrocytes to proliferate and exert their functions. Although TSHR is predominantly expressed in thyrocytes, several studies have revealed that functional TSHR can also be detected in many extra-thyroid tissues, such as primary ovarian and hepatic tissues as well as their corresponding malignancies. Recent advances in cancer biology further raise the possibility of utilizing TSH and/or TSHR as a therapeutic target or as an informative index to predict treatment responses in cancer patients. The TSH/TSHR cascade has been considered a pivotal modulator for carcinogenesis and/or tumor progression in these cancers. TSHR belongs to a sub-group of family A G-protein-coupled receptors (GPCRs), which activate a bundle of well-defined signaling transduction pathways to enhance cell renewal in response to external stimuli. In this review, recent findings regarding the molecular basis of TSH/TSHR functions in either thyroid or extra-thyroid tissues and the potential of directly targeting TSHR as an anticancer strategy are summarized and discussed. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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14 pages, 880 KiB  
Review
The Network of Angiotensin Receptors in Breast Cancer
by Filippo Acconcia
Cells 2020, 9(6), 1336; https://doi.org/10.3390/cells9061336 - 27 May 2020
Cited by 20 | Viewed by 6834
Abstract
The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system physiology. The RAS is a complicated network of G-protein coupled receptors (GPCRs) (i.e., AT1R, AT2R, MASR, and MRGD) orchestrating the effects of [...] Read more.
The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system physiology. The RAS is a complicated network of G-protein coupled receptors (GPCRs) (i.e., AT1R, AT2R, MASR, and MRGD) orchestrating the effects of several hormones (i.e., angiotensin II, angiotensin (1–7), and alamandine) produced by protease-based transmembrane receptors (ACE1 and ACE2). Two signaling axes have been identified in the RAS endocrine system that mediate the proliferative actions of angiotensin II (i.e., the AT1R-based pathway) or the anti-proliferative effects of RAS hormones (i.e., the AT2R-, MAS-, and MRGD-based pathways). Disruption of the balance between these two axes can cause different diseases (e.g., cardiovascular pathologies and the severe acute respiratory syndrome coronavirus 2- (SARS-CoV-2)-based COVID-19 disease). It is now accepted that all the components of the RAS endocrine system are expressed in cancer, including cancer of the breast. Breast cancer (BC) is a multifactorial pathology for which there is a continuous need to identify novel drugs. Here, I reviewed the possible roles of both axes of the RAS endocrine network as potential druggable pathways in BC. Remarkably, the analysis of the current knowledge of the different GPCRs of the RAS molecular system not only confirms that AT1R could be considered a drug target and that its inhibition by losartan and candesartan could be useful in the treatment of BC, but also identifies Mas-related GPCR member D (MRGD) as a druggable protein. Overall, the RAS of GPCRs offers multifaceted opportunities for the development of additional compounds for the treatment of BC. Full article
(This article belongs to the Special Issue Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives)
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