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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—Series II

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 13320

Special Issue Editors

Prof. Dr. Marcello Maggiolini

E-Mail Website
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
Dr. Rosamaria Lappano

E-Mail Website
Guest Editor
Associate Professor, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Cosenza, Italy
Interests: hormones; hormone receptors; growth factors; RTKs; GPCRs; cancer microenvironment; CAFs; hypoxia; signal transduction; endocrine-related cancers
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 signaling 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 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 opportunity to identify 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. Dr. Marcello Maggiolini
Dr. Rosamaria Lappano
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

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Related Special Issue

Published Papers (6 papers)

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Editorial

Jump to: Research, Review, Other

6 pages, 243 KiB  
Editorial
Role of the G Protein-Coupled Receptors in Cancer and Stromal Cells: From Functions to Novel Therapeutic Perspectives
by Rosamaria Lappano and Marcello Maggiolini
Cells 2023, 12(4), 626; https://doi.org/10.3390/cells12040626 - 15 Feb 2023
Cited by 2 | Viewed by 1558
Abstract
G protein-coupled receptors (GPCRs) are transmembrane signal transducers that regulate a plethora of physiological and pathological processes [...] 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—Series II)

Research

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27 pages, 8078 KiB  
Article
Proteomic Analyses of the G Protein-Coupled Estrogen Receptor GPER1 Reveal Constitutive Links to Endoplasmic Reticulum, Glycosylation, Trafficking, and Calcium Signaling
by Maryam Ahmadian Elmi, Nasrin Motamed and Didier Picard
Cells 2023, 12(21), 2571; https://doi.org/10.3390/cells12212571 - 3 Nov 2023
Viewed by 2181
Abstract
The G protein-coupled estrogen receptor 1 (GPER1) has been proposed to mediate rapid responses to the steroid hormone estrogen. However, despite a strong interest in its potential role in cancer, whether it is indeed activated by estrogen and how this works remain controversial. [...] Read more.
The G protein-coupled estrogen receptor 1 (GPER1) has been proposed to mediate rapid responses to the steroid hormone estrogen. However, despite a strong interest in its potential role in cancer, whether it is indeed activated by estrogen and how this works remain controversial. To provide new tools to address these questions, we set out to determine the interactome of exogenously expressed GPER1. The combination of two orthogonal methods, namely APEX2-mediated proximity labeling and immunoprecipitation followed by mass spectrometry, gave us high-confidence results for 73 novel potential GPER1 interactors. We found that this GPER1 interactome is not affected by estrogen, a result that mirrors the constitutive activity of GPER1 in a functional assay with a Rac1 sensor. We specifically validated several hits highlighted by a gene ontology analysis. We demonstrate that CLPTM1 interacts with GPER1 and that PRKCSH and GANAB, the regulatory and catalytic subunits of α-glucosidase II, respectively, associate with CLPTM1 and potentially indirectly with GPER1. An imbalance in CLPTM1 levels induces nuclear association of GPER1, as does the overexpression of PRKCSH. Moreover, we show that the Ca2+ sensor STIM1 interacts with GPER1 and that upon STIM1 overexpression and depletion of Ca2+ stores, GPER1 becomes more nuclear. Thus, these new GPER1 interactors establish interesting connections with membrane protein maturation, trafficking, and calcium signaling. 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—Series II)
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14 pages, 3766 KiB  
Article
GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma
by Maria Eugenia Gallo Cantafio, Roberta Torcasio, Francesca Scionti, Maria Mesuraca, Domenica Ronchetti, Mariaelena Pistoni, Dina Bellizzi, Giuseppe Passarino, Eugenio Morelli, Antonino Neri, Giuseppe Viglietto and Nicola Amodio
Cells 2023, 12(18), 2226; https://doi.org/10.3390/cells12182226 - 7 Sep 2023
Viewed by 1722
Abstract
G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we [...] Read more.
G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we show that GPER1 mRNA is down-regulated in plasma cells from overt multiple myeloma (MM) and plasma cell leukemia patients as compared to normal donors or pre-malignant conditions (monoclonal gammopathy of undetermined significance and smoldering MM); moreover, lower GPER1 expression associates with worse overall survival of MM patients. Using the clinically applicable GPER1-selective agonist G-1, we demonstrate that the pharmacological activation of GPER1 triggered in vitro anti-MM activity through apoptosis induction, also overcoming the protective effects exerted by bone marrow stromal cells. Noteworthy, G-1 treatment reduced in vivo MM growth in two distinct xenograft models, even bearing bortezomib-resistant MM cells. Mechanistically, G-1 upregulated the miR-29b oncosuppressive network, blunting an established miR-29b-Sp1 feedback loop operative in MM cells. Overall, this study highlights the druggability of GPER1 in MM, providing the first preclinical framework for further development of GPER1 agonists to treat this malignancy. 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—Series II)
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19 pages, 2501 KiB  
Article
The Expression Pattern of Adhesion G Protein-Coupled Receptor F5 Is Related to Cell Adhesion and Metastatic Pathways in Colorectal Cancer—Comprehensive Study Based on In Silico Analysis
by Huining Kang, Jakub Fichna, Ksenia Matlawska-Wasowska and Damian Jacenik
Cells 2022, 11(23), 3876; https://doi.org/10.3390/cells11233876 - 1 Dec 2022
Cited by 4 | Viewed by 1955
Abstract
Adhesion G protein-coupled receptor F5 (ADGRF5) is involved inthe neoplastic transformation of some cancer types. However, the significance of ADGRF5 expression signature and the impact of signaling pathways mediated by ADGRF5 during neoplastic transformation of the colon and colorectal cancer (CRC) progression has [...] Read more.
Adhesion G protein-coupled receptor F5 (ADGRF5) is involved inthe neoplastic transformation of some cancer types. However, the significance of ADGRF5 expression signature and the impact of signaling pathways mediated by ADGRF5 during neoplastic transformation of the colon and colorectal cancer (CRC) progression has been poorly examined. Using Gene Expression Omnibus and The Cancer Genome Atlas datasets, we showed that ADGRF5 is overexpressed in the colons of patients with CRC. In line, combined analysis of ADGRF5 expression with clinical characterization revealed an increased expression of ADGRF5 in patients with more advanced stages of CRC compared to patients with early stages of CRC. The Spearman correlation analysis documented numerous genes positively and negatively correlated with the expression pattern of ADGRF5 in the colon of patients with CRC. In the colon of CRC patients, the expression signature of ADGRF5 was associated with genes participating in phosphatidylinositol 3-kinase/Akt, focal adhesion, cell adhesion molecules, and ribosome signaling pathways. Of note, ADGRF5 expression correlated with the levels of tumor-infiltrating immune cells in the colon of CRC patients. Moreover, we found that CRC patients with high expression of ADGRF5 had a significantly lower probability of overall survival and disease-free survival. In conclusion, our results support the prognostic value of ADGRF5 and its potent therapeutic implication in CRC. 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—Series II)
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Review

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27 pages, 4308 KiB  
Review
The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer
by Keith A. Hall and Edward J. Filardo
Cells 2023, 12(20), 2460; https://doi.org/10.3390/cells12202460 - 16 Oct 2023
Cited by 9 | Viewed by 3172
Abstract
Estrogens have been implicated in the pathogenesis of various cancers, with increasing concern regarding the overall rising incidence of disease and exposure to environmental estrogens. Estrogens, both endogenous and environmental, manifest their actions through intracellular and plasma membrane receptors, named ERα, ERβ, and [...] Read more.
Estrogens have been implicated in the pathogenesis of various cancers, with increasing concern regarding the overall rising incidence of disease and exposure to environmental estrogens. Estrogens, both endogenous and environmental, manifest their actions through intracellular and plasma membrane receptors, named ERα, ERβ, and GPER. Collectively, they act to promote a broad transcriptional response that is mediated through multiple regulatory enhancers, including estrogen response elements (EREs), serum response elements (SREs), and cyclic AMP response elements (CREs). Yet, the design and rational assignment of antiestrogen therapy for breast cancer has strictly relied upon an endogenous estrogen–ER binary rubric that does not account for environmental estrogens or GPER. New endocrine therapies have focused on the development of drugs that degrade ER via ER complex destabilization or direct enzymatic ubiquitination. However, these new approaches do not broadly treat all cancer-involved receptors, including GPER. The latter is concerning since GPER is directly associated with tumor size, distant metastases, cancer stem cell activity, and endocrine resistance, indicating the importance of targeting this receptor to achieve a more complete therapeutic response. This review focuses on the critical importance and value of GPER-targeted therapeutics as part of a more holistic approach to the treatment of estrogen-driven malignancies. 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—Series II)
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Other

12 pages, 1059 KiB  
Perspective
Promising Perspectives of the Antiproliferative GPER Inverse Agonist ERα17p in Breast Cancer
by Marilena Kampa, Rosamaria Lappano, Fedora Grande, Bruno Rizzuti, Marcello Maggiolini, Elias Castanas and Yves Jacquot
Cells 2023, 12(4), 653; https://doi.org/10.3390/cells12040653 - 18 Feb 2023
Cited by 6 | Viewed by 1891
Abstract
The estrogen receptor α (ERα) corresponds to a large platform in charge of the recruitment of a panel of molecules, including steroids and related heterocyclic derivatives, oligonucleotides, peptides and proteins. Its 295–311 region is particularly targeted by post-translational modifications, suggesting that it could [...] Read more.
The estrogen receptor α (ERα) corresponds to a large platform in charge of the recruitment of a panel of molecules, including steroids and related heterocyclic derivatives, oligonucleotides, peptides and proteins. Its 295–311 region is particularly targeted by post-translational modifications, suggesting that it could be crucial for the control of transcription. In addition to anionic phospholipids, the ERα 295–311 fragment interacts with Ca2+-calmodulin, the heat shock protein 70 (Hsp70), ERα and possibly importins. More recently, we have demonstrated that it is prone to interacting with the G-protein-coupled estrogen receptor (GPER). In light of these observations, the pharmacological profile of the corresponding peptide, namely ERα17p, has been explored in breast cancer cells. Remarkably, it exerts apoptosis through GPER and induces a significant decrease (more than 50%) of the size of triple-negative breast tumor xenografts in mice. Herein, we highlight not only the promising therapeutic perspectives in the use of the first peptidic GPER modulator ERα17p, but also the opportunity to modulate GPER for clinical purposes. 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—Series II)
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