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Cells
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G-Protein Coupled Receptors in Cancer
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G-Protein Coupled Receptors in Cancer

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

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 44369

Special Issue Editor

Dr. Anthony Ashton

E-Mail Website
Guest Editor
Division of Cardiovascular Medicine, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
Interests: G-protein coupled receptors; Angiogenesis; Cardiac remodeling; Pregnancy; Placentation

Special Issue Information

Dear Colleagues,

G-protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. Signaling by heterotrimeric G-proteins begins when ligand binding to the GPCR triggers a conformational change promoting proximity of the GEF domain and the GDP-bound heterotrimeric G-protein. GTP exchange liberates the a-subunit from the bg-subunits and initiates signal transduction. G-protein inactivation occurs when GTP hydrolyses to GDP in the a-subunit (promoted by RGS proteins) and the bg-subunits re-associate. The pathway may also be inhibited by phosphorylation of the GPCR by protein kinases, the subsequent binding of arrestin proteins, and internalization of the receptor through clathrin-coated pits. Despite mediating a cornucopia of physiological processes, the role of GPCRs in tumor biology is underappreciated. GPCRs, their ligands, and downstream effectors significantly regulate tumor growth and metastasis but influence tumor and stromal cells alike. The normal physiological functions of GPCRs are often hijacked by malignant cells to promote cell survival and proliferation, immune cell evasion, local and distant invasion, and recruitment of blood vessels.

This Special Issue of Cells invites both original research and review articles that examine the role of GPCRs, their G-protein targets and their regulatory apparatus (RGSs, GRKs) in tumorigenesis (including the role of point mutations, gene overexpression, and epigenetic promoter silencing), and stromal and immune responses in the tumor milieu. We will also discuss the unique opportunities for targeting GPCRs for therapeutic gain in cancers without current therapy and those refractory to current approaches.

Dr. Anthony Ashton
Guest Editor

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Keywords

  • GPCR
  • arrestin
  • RGS
  • GRK
  • tumorigenesis
  • inflammation
  • angiogenesis
  • metastasis

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Published Papers (9 papers)

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Research

Jump to: Review

23 pages, 4399 KiB  
Article
Expression of the Human Serotonin 5-HT7 Receptor Rescues Phenotype Profile and Restores Dysregulated Biomarkers in a Drosophila melanogaster Glioma Model
by Florestan Courant, Marion Maravat, Wanyin Chen, David Gosset, Lauren Blot, Nadège Hervouet-Coste, Vincent Sarou-Kanian, Séverine Morisset-Lopez and Martine Decoville
Cells 2022, 11(8), 1281; https://doi.org/10.3390/cells11081281 - 9 Apr 2022
Cited by 1 | Viewed by 3087
Abstract
Gliomas are the most common primary brain tumors in adults. Significant progress has been made in recent years in identifying the molecular alterations involved in gliomas. Among them, an amplification/overexpression of the EGFR (Epidermal Growth Factor Receptor) proto-oncogene and its associated signaling pathways [...] Read more.
Gliomas are the most common primary brain tumors in adults. Significant progress has been made in recent years in identifying the molecular alterations involved in gliomas. Among them, an amplification/overexpression of the EGFR (Epidermal Growth Factor Receptor) proto-oncogene and its associated signaling pathways have been widely described. However, current treatments remain ineffective for glioblastomas, the most severe forms. Thus, the identification of other pharmacological targets could open new therapeutic avenues. We used a glioma model in Drosophila melanogaster that results from the overexpression of constitutively active forms of EGFR and PI3K specifically in glial cells. We observed hyperproliferation of glial cells that leads to an increase in brain size and lethality at the third instar larval stage. After expression of the human serotonin 5-HT7 receptor in this glioma model, we observed a decrease in larval lethality associated with the presence of surviving adults and a return to a normal morphology of brain for some Drosophila. Those phenotypic changes are accompanied by the normalization of certain metabolic biomarkers measured by High-Resolution Magic Angle Spinning NMR (HR-MAS NMR). The 5-HT7R expression in glioma also restores some epigenetic modifications and characteristic markers of the signaling pathways associated with tumor growth. This study demonstrates the role of the serotonin 5-HT7 receptor as a tumor suppressor gene which is in agreement with transcriptomic analysis obtained on human glioblastomas. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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18 pages, 2600 KiB  
Article
Identification of Dysregulated Expression of G Protein Coupled Receptors in Endocrine Tumors by Bioinformatics Analysis: Potential Drug Targets?
by Valentine Suteau, Mathilde Munier, Rym Ben Boubaker, Méline Wery, Daniel Henrion, Patrice Rodien and Claire Briet
Cells 2022, 11(4), 703; https://doi.org/10.3390/cells11040703 - 17 Feb 2022
Cited by 3 | Viewed by 3729
Abstract
Background: Many studies link G protein-coupled receptors (GPCRs) to cancer. Some endocrine tumors are unresponsive to standard treatment and/or require long-term and poorly tolerated treatment. This study explored, by bioinformatics analysis, the tumoral profiling of the GPCR transcriptome to identify potential targets in [...] Read more.
Background: Many studies link G protein-coupled receptors (GPCRs) to cancer. Some endocrine tumors are unresponsive to standard treatment and/or require long-term and poorly tolerated treatment. This study explored, by bioinformatics analysis, the tumoral profiling of the GPCR transcriptome to identify potential targets in these tumors aiming at drug repurposing. Methods: We explored the GPCR differentially expressed genes (DEGs) from public datasets (Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA)). The GEO datasets were available for two medullary thyroid cancers (MTCs), eighty-seven pheochromocytomas (PHEOs), sixty-one paragangliomas (PGLs), forty-seven pituitary adenomas and one-hundred-fifty adrenocortical cancers (ACCs). The TCGA dataset covered 92 ACCs. We identified GPCRs targeted by approved drugs from pharmacological databases (ChEMBL and DrugBank). Results: The profiling of dysregulated GPCRs was tumor specific. In MTC, we found 14 GPCR DEGs, including an upregulation of the dopamine receptor (DRD2) and adenosine receptor (ADORA2B), which were the target of many drugs. In PGL, seven GPCR genes were downregulated, including vasopressin receptor (AVPR1A) and PTH receptor (PTH1R), which were targeted by approved drugs. In ACC, PTH1R was also downregulated in both the GEO and TCGA datasets and was the target of osteoporosis drugs. Conclusions: We highlight specific GPCR signatures across the major endocrine tumors. These data could help to identify new opportunities for drug repurposing. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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11 pages, 2660 KiB  
Article
Expression of Proton-Sensitive GPR31, GPR151, TASK1 and TASK3 in Common Skin Tumors
by Antonia Förch, Susanne Wallner, Florian Zeman, Tobias Ettl, Christoph Brochhausen and Stephan Schreml
Cells 2022, 11(1), 27; https://doi.org/10.3390/cells11010027 - 23 Dec 2021
Cited by 3 | Viewed by 3510
Abstract
TWIK-related acid-sensitive potassium channels TASK1 and TASK3, as well as the G-protein-coupled receptors GPR31 and GPR151, are proton-sensitive membrane proteins. They can be activated or inhibited by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, [...] Read more.
TWIK-related acid-sensitive potassium channels TASK1 and TASK3, as well as the G-protein-coupled receptors GPR31 and GPR151, are proton-sensitive membrane proteins. They can be activated or inhibited by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of TASK1, TASK3, GPR31 and GPR151 in squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), nevus cell nevi (NCN), and malignant melanomas (MMs). We performed immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express TASK1/3 and GPR31/151. The results show that BCCs are often negative for GPR31/151 as well as for TASK1/3, while nearly all SCCs express these markers. MMs and NCN show similar expression patterns. However, some tumors show a decreasing TASK1/3 expression in deeper dermal tumor tissue, while GPCRs were expressed more evenly. The lower frequency of GPR31/151 and TSAK1/3 expression in BCCs when compared to SCCs is a novel histological feature distinguishing these two entities. Moreover, BCCs also show lower expression of GPR31/151 and TASK1/3 as compared to NCN and MMs. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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Review

Jump to: Research

24 pages, 1590 KiB  
Review
The RAL Enigma: Distinct Roles of RALA and RALB in Cancer
by Dillon S. Richardson, Jonathan M. Spehar, David T. Han, Prathik A. Chakravarthy and Steven T. Sizemore
Cells 2022, 11(10), 1645; https://doi.org/10.3390/cells11101645 - 14 May 2022
Cited by 10 | Viewed by 4617
Abstract
RALA and RALB are highly homologous small G proteins belonging to the RAS superfamily. Like other small GTPases, the RALs are molecular switches that can be toggled between inactive GDP-bound and active GTP-bound states to regulate diverse and critical cellular functions such as [...] Read more.
RALA and RALB are highly homologous small G proteins belonging to the RAS superfamily. Like other small GTPases, the RALs are molecular switches that can be toggled between inactive GDP-bound and active GTP-bound states to regulate diverse and critical cellular functions such as vesicle trafficking, filopodia formation, mitochondrial fission, and cytokinesis. The RAL paralogs are activated and inactivated by a shared set of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) and utilize similar sets of downstream effectors. In addition to their important roles in normal cell biology, the RALs are known to be critical mediators of cancer cell survival, invasion, migration, and metastasis. However, despite their substantial similarities, the RALs often display striking functional disparities in cancer. RALA and RALB can have redundant, unique, or even antagonistic functions depending on cancer type. The molecular basis for these discrepancies remains an important unanswered question in the field of cancer biology. In this review we examine the functions of the RAL paralogs in normal cellular physiology and cancer biology with special consideration provided to situations where the roles of RALA and RALB are non-redundant. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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25 pages, 3205 KiB  
Review
Antiplatelet Agents Affecting GPCR Signaling Implicated in Tumor Metastasis
by Gianenrico Rovati, Annalisa Contursi, Annalisa Bruno, Stefania Tacconelli, Patrizia Ballerini and Paola Patrignani
Cells 2022, 11(4), 725; https://doi.org/10.3390/cells11040725 - 18 Feb 2022
Cited by 6 | Viewed by 4302
Abstract
Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different [...] Read more.
Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial–mesenchymal-like transition. Therefore, agents that affect platelet activation can potentially restrain these prometastatic mechanisms. Although the primary adhesion of platelets to cancer cells is mainly independent of G protein-mediated signaling, soluble mediators released from platelets, such as ADP, thromboxane (TX) A2, and prostaglandin (PG) E2, act through G protein-coupled receptors (GPCRs) to cause the activation of more additional platelets and drive metastatic signaling pathways in cancer cells. In this review, we examine the contribution of the GPCRs of platelets and cancer cells in the development of cancer metastasis. Finally, the possible use of agents affecting GPCR signaling pathways as antimetastatic agents is discussed. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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50 pages, 2285 KiB  
Review
C-C Chemokine Receptor 7 in Cancer
by Colin A. Bill, Christopher M. Allen and Charlotte M. Vines
Cells 2022, 11(4), 656; https://doi.org/10.3390/cells11040656 - 14 Feb 2022
Cited by 16 | Viewed by 3795
Abstract
C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis of cells and tissue organization. Since under homeostatic conditions, CCR7 promotes migration of immune cells to lymph [...] Read more.
C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis of cells and tissue organization. Since under homeostatic conditions, CCR7 promotes migration of immune cells to lymph nodes, questions immediately arose regarding the ability of CCR7 to direct migration of cancer cells to lymph nodes. The literature since 2000 was examined to determine to what extent the expression of CCR7 in malignant tumors promoted migration to the lymph nodes. The data indicated that in different cancers, CCR7 plays distinct roles in directing cells to lymph nodes, the skin or to the central nervous system. In certain tumors, it may even serve a protective role. Future studies should focus on defining mechanisms that differentially regulate the unfavorable or beneficial role that CCR7 plays in cancer pathophysiology, to be able to improve outcomes in patients who harbor CCR7-positive cancers. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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16 pages, 977 KiB  
Review
Role of ADGRG1/GPR56 in Tumor Progression
by Kwai-Fong Ng, Tse-Ching Chen, Martin Stacey and Hsi-Hsien Lin
Cells 2021, 10(12), 3352; https://doi.org/10.3390/cells10123352 - 29 Nov 2021
Cited by 12 | Viewed by 4209
Abstract
Cellular communication plays a critical role in diverse aspects of tumorigenesis including tumor cell growth/death, adhesion/detachment, migration/invasion, angiogenesis, and metastasis. G protein-coupled receptors (GPCRs) which constitute the largest group of cell surface receptors are known to play fundamental roles in all these processes. [...] Read more.
Cellular communication plays a critical role in diverse aspects of tumorigenesis including tumor cell growth/death, adhesion/detachment, migration/invasion, angiogenesis, and metastasis. G protein-coupled receptors (GPCRs) which constitute the largest group of cell surface receptors are known to play fundamental roles in all these processes. When considering the importance of GPCRs in tumorigenesis, the adhesion GPCRs (aGPCRs) are unique due to their hybrid structural organization of a long extracellular cell-adhesive domain and a seven-transmembrane signaling domain. Indeed, aGPCRs have been increasingly shown to be associated with tumor development by participating in tumor cell interaction and signaling. ADGRG1/GPR56, a representative tumor-associated aGPCR, is recognized as a potential biomarker/prognostic factor of specific cancer types with both tumor-suppressive and tumor-promoting functions. We summarize herein the latest findings of the role of ADGRG1/GPR56 in tumor progression. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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42 pages, 1028 KiB  
Review
An Insight into GPCR and G-Proteins as Cancer Drivers
by Preeti Kumari Chaudhary and Soochong Kim
Cells 2021, 10(12), 3288; https://doi.org/10.3390/cells10123288 - 24 Nov 2021
Cited by 76 | Viewed by 10946
Abstract
G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including tumor growth and metastasis. Various molecules such as hormones, lipids, peptides, and neurotransmitters activate GPCRs that enable the coupling of [...] Read more.
G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including tumor growth and metastasis. Various molecules such as hormones, lipids, peptides, and neurotransmitters activate GPCRs that enable the coupling of these receptors to highly specialized transducer proteins, called G-proteins, and initiate multiple signaling pathways. Integration of these intricate networks of signaling cascades leads to numerous biochemical responses involved in diverse pathophysiological activities, including cancer development. While several studies indicate the role of GPCRs in controlling various aspects of cancer progression such as tumor growth, invasion, migration, survival, and metastasis through its aberrant overexpression, mutations, or increased release of agonists, the explicit mechanisms of the involvement of GPCRs in cancer progression is still puzzling. This review provides an insight into the various responses mediated by GPCRs in the development of cancers, the molecular mechanisms involved and the novel pharmacological approaches currently preferred for the treatment of cancer. Thus, these findings extend the knowledge of GPCRs in cancer cells and help in the identification of therapeutics for cancer patients. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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13 pages, 986 KiB  
Review
Adenosine Receptor Antagonists to Combat Cancer and to Boost Anti-Cancer Chemotherapy and Immunotherapy
by Rafael Franco, Rafael Rivas-Santisteban, Gemma Navarro and Irene Reyes-Resina
Cells 2021, 10(11), 2831; https://doi.org/10.3390/cells10112831 - 21 Oct 2021
Cited by 26 | Viewed by 4426
Abstract
Extracellular adenosine accumulates in the environment of numerous tumors. For years, this fact has fueled preclinical research to determine whether adenosine receptors (ARs) could be the target to fight cancer. The four ARs discovered so far, A1, A2A, A [...] Read more.
Extracellular adenosine accumulates in the environment of numerous tumors. For years, this fact has fueled preclinical research to determine whether adenosine receptors (ARs) could be the target to fight cancer. The four ARs discovered so far, A1, A2A, A2B and A3, belong to the class A family of G protein-coupled receptors (GPCRs) and all four have been involved in one way or another in regulating tumor progression. Prompted by the successful anti-cancer immunotherapy, the focus was placed on the ARs more involved in regulation of immune cell differentiation and activation and that are able to establish molecular and functional interactions. This review focuses on the potential of A2A and A2B receptor antagonists in cancer control and in boosting anti-cancer chemotherapy and immunotherapy. The article also overviews the ongoing clinical trials in which A2AR and A2BR ligands are being tested in anti-cancer therapy. Full article
(This article belongs to the Special Issue G-Protein Coupled Receptors in Cancer)
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