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Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 95838

Special Issue Editors


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Guest Editor
Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel
Interests: G-protein coupled receptors (GPCRs) involvement in tumor biology; the role of protease-activated receptors (PARs) oncogenes in canmcer
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Guest Editor
Inflammation Research Network–Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
Interests: molecular pharmacology; medicine; inflammation; signal transduction; receptors; molecular biology; cell biology; mRNA expression

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCR) are seven transmembrane proteins initiating a wide range of signals that affect numerous physiological and pathological processes. As therapeutic targets, they have accounted for nearly 30% of the successful receptor-based drug treatments of disorders ranging from hypertension and allergy to clinical depression.

While a great deal of information has been gathered with regard to their structure, classification, signaling properties and unique mode of "biased" (or "functionally selective") GPCR signalling pathways, it is now timely to define their role in tumor biology. Despite the fact that many GPCRs belonging to different subclasses have emerged with central roles in cancer development, as yet no known cancer-therapeutic GPCR-targeted drug is in clinical practice. Of note, the genomic, transcriptomic and immunohistochemical analyses of tumour tissues has revealed a 20% incidence of GPCR mutations in many cancers; and an upregulation of wild-type GPCRs has been documented, due to multiple mechanisms. Thus, an increased understanding of the ways GPCRs can act as cancer drivers is highly warranted.

The Need Met by This Special Issue

Given the above information, it is thus the goal of this Special Issue to highlight the roles that GPCRs may play in tumor growth, invasion, metastasis and survival at both the primary and secondary metastatic sites, including the cancer stem cell niche. It is intended to emphasize the great potential of targeting GPCRs to treat cancer.

For each of a number of selected GPCRs, including the adhesion and frizzled (FZD) families, along with the Class A, B and C receptors, contributors are asked to provide a concise overview of the current receptor cell biology, their potential as cancer drivers and their potential as therapeutic targets in the setting of cancer.

Prof. Dr. Rachel Bar-Shavit
Prof. Dr. Morley D. Hollenberg
Guest Editors

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Keywords

  • proteinase-mediated signaling

  • proteinase-activated recepgors (PARs)

  • biased signaling

  • G-protein-coupled receptors (GPCRs)

  • cell growth

  • invasion

  • metastasis

  • microenvironment proteinases

  • wnt/beta-catenin and GPCRs

  • stem cells

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Published Papers (11 papers)

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14 pages, 4952 KiB  
Article
The Effect of GPRC5a on the Proliferation, Migration Ability, Chemotherapy Resistance, and Phosphorylation of GSK-3β in Pancreatic Cancer
by Bin Liu, Hai Yang, Christian Pilarsky and Georg F. Weber
Int. J. Mol. Sci. 2018, 19(7), 1870; https://doi.org/10.3390/ijms19071870 - 26 Jun 2018
Cited by 32 | Viewed by 5921
Abstract
Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related death, and personalized targeted cancer therapy is becoming a promising treatment strategy for PaCa. The central approach of targeted therapy is to find a targetable key and an effective targeting method. In this [...] Read more.
Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related death, and personalized targeted cancer therapy is becoming a promising treatment strategy for PaCa. The central approach of targeted therapy is to find a targetable key and an effective targeting method. In this study, the importance of GPRC5a (the G-protein-coupled receptor family C, member 5, group A) was identified using data mining methods based on published datasets. After analysis of the basic expression of GPRC5a in normal pancreas tissue and various PaCa cell lines, gene editing of GPRC5a in the human PaCa cell line MIA PaCa-2 and the mouse PaCa cell line TB32047 was performed using CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated proteins 9) to investigate the influence of GPRC5a on the proliferation and migration of PaCa cells as well as its effects on chemotherapy drug resistance. The results showed that GPRC5a was upregulated in PaCa tissues and various PaCa cell lines. Knockout of GPRC5a reduced the proliferation and migration ability of PaCa cell lines and suppressed the chemotherapy drug resistance of gemcitabine, oxaliplatin, and fluorouracil in PaCa cells. The phosphorylation of GSK-3β (Glycogen synthase kinase-3β) was found to be upregulated in the MIA PaCa-2 and TB32047 cells after GPRC5a knockout. In conclusion, GPRC5a was upregulated in PaCa leading to an enhanced drug resistance in PaCa cells. These results provide for the first time a theoretical basis for the development of an improved PaCa targeted therapy. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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Review

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17 pages, 3103 KiB  
Review
GPR68: An Emerging Drug Target in Cancer
by Shu Z. Wiley, Krishna Sriram, Cristina Salmerón and Paul A. Insel
Int. J. Mol. Sci. 2019, 20(3), 559; https://doi.org/10.3390/ijms20030559 - 28 Jan 2019
Cited by 58 | Viewed by 9751
Abstract
GPR68 (or ovarian cancer G protein-coupled receptor 1, OGR1) is a proton-sensing G-protein-coupled receptor (GPCR) that responds to extracellular acidity and regulates a variety of cellular functions. Acidosis is considered a defining hallmark of the tumor microenvironment (TME). GPR68 expression is highly upregulated [...] Read more.
GPR68 (or ovarian cancer G protein-coupled receptor 1, OGR1) is a proton-sensing G-protein-coupled receptor (GPCR) that responds to extracellular acidity and regulates a variety of cellular functions. Acidosis is considered a defining hallmark of the tumor microenvironment (TME). GPR68 expression is highly upregulated in numerous types of cancer. Emerging evidence has revealed that GPR68 may play crucial roles in tumor biology, including tumorigenesis, tumor growth, and metastasis. This review summarizes current knowledge regarding GPR68—its expression, regulation, signaling pathways, physiological roles, and functions it regulates in human cancers (including prostate, colon and pancreatic cancer, melanoma, medulloblastoma, and myelodysplastic syndrome). The findings provide evidence for GPR68 as a potentially novel therapeutic target but in addition, we note challenges in developing drugs that target GPR68. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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36 pages, 5606 KiB  
Review
GPCR Modulation in Breast Cancer
by Rosamaria Lappano, Yves Jacquot and Marcello Maggiolini
Int. J. Mol. Sci. 2018, 19(12), 3840; https://doi.org/10.3390/ijms19123840 - 2 Dec 2018
Cited by 31 | Viewed by 9675
Abstract
Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. [...] Read more.
Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. In contrast, triple-negative breast cancer (TNBC), a highly heterogeneous disease that may account for up to 24% of all newly diagnosed cases, is hormone-independent and characterized by a poor prognosis. As drug resistance is common in all breast cancer subtypes despite the different treatment modalities, novel therapies targeting signaling transduction pathways involved in the processes of breast carcinogenesis, tumor promotion and metastasis have been subject to accurate consideration. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors involved in the development and progression of many tumors including breast cancer. Here we discuss data regarding GPCR-mediated signaling, pharmacological properties and biological outputs toward breast cancer tumorigenesis and metastasis. Furthermore, we address several drugs that have shown an unexpected opportunity to interfere with GPCR-based breast tumorigenic signals. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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21 pages, 2797 KiB  
Review
Transcriptional Landscape of PARs in Epithelial Malignancies
by Jeetendra Kumar Nag and Rachel Bar-Shavit
Int. J. Mol. Sci. 2018, 19(11), 3451; https://doi.org/10.3390/ijms19113451 - 2 Nov 2018
Cited by 10 | Viewed by 4716
Abstract
G protein-coupled receptors (GPCRs), the largest family of cell receptors, act as important regulators of diverse signaling pathways. Our understanding of the impact of GPCRs in tumors is emerging, yet there is no therapeutic platform based on GPCR driver genes. As cancer progresses, [...] Read more.
G protein-coupled receptors (GPCRs), the largest family of cell receptors, act as important regulators of diverse signaling pathways. Our understanding of the impact of GPCRs in tumors is emerging, yet there is no therapeutic platform based on GPCR driver genes. As cancer progresses, it disrupts normal epithelial organization and maintains the cells outside their normal niche. The dynamic and flexible microenvironment of a tumor contains both soluble and matrix-immobilized proteases that contribute to the process of cancer advancement. An example is the activation of cell surface protease-activated receptors (PARs). Mammalian PARs are a subgroup of GPCRs that form a family of four members, PAR1–4, which are uniquely activated by proteases found in the microenvironment. PAR1 and PAR2 play central roles in tumor biology, and PAR3 acts as a coreceptor. The significance of PAR4 in neoplasia is just beginning to emerge. PAR1 has been shown to be overexpressed in malignant epithelia, in direct correlation with tumor aggressiveness, but there is no expression in normal epithelium. In this review, the involvement of key transcription factors such as Egr1, p53, Twist, AP2, and Sp1 that control PAR1 expression levels specifically, as well as hormone transcriptional regulation by both estrogen receptors (ER) and androgen receptors (AR) are discussed. The cloning of the human protease-activated receptor 2; Par2 (hPar2) promoter region and transcriptional regulation of estrogen (E2) via binding of the E2–ER complex to estrogen response elements (ERE) are shown. In addition, evidence that TEA domain 4 (TEAD4) motifs are present within the hPar2 promoter is presented since the YAP oncogene, which plays a central part in tumor etiology, acts via the TEAD4 transcription factor. As of now, no information is available on regulation of the hPar3 promoter. With regard to hPar4, only data showing CpG methylation promoter regulation is available. Characterization of the PAR transcriptional landscape may identify powerful targets for cancer therapies. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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16 pages, 1832 KiB  
Review
Protease-Activated Receptor 1 as Therapeutic Target in Breast, Lung, and Ovarian Cancer: Pepducin Approach
by Lidija Covic and Athan Kuliopulos
Int. J. Mol. Sci. 2018, 19(8), 2237; https://doi.org/10.3390/ijms19082237 - 31 Jul 2018
Cited by 41 | Viewed by 7897
Abstract
The G-protein coupled receptors (GPCRs) belong to a large family of diverse receptors that are well recognized as pharmacological targets. However, very few of these receptors have been pursued as oncology drug targets. The Protease-activated receptor 1 (PAR1), which is a G-protein coupled [...] Read more.
The G-protein coupled receptors (GPCRs) belong to a large family of diverse receptors that are well recognized as pharmacological targets. However, very few of these receptors have been pursued as oncology drug targets. The Protease-activated receptor 1 (PAR1), which is a G-protein coupled receptor, has been shown to act as an oncogene and is an emerging anti-cancer drug target. In this paper, we provide an overview of PAR1’s biased signaling role in metastatic cancers of the breast, lungs, and ovaries and describe the development of PAR1 inhibitors that are currently in clinical use to treat acute coronary syndromes. PAR1 inhibitor PZ-128 is in a Phase II clinical trial and is being developed to prevent ischemic and thrombotic complication of patients undergoing cardiac catheterization. PZ-128 belongs to a new class of cell-penetrating, membrane-tethered peptides named pepducins that are based on the intracellular loops of receptors targeting the receptor G-protein interface. Application of PZ-128 as an anti-metastatic and anti-angiogenic therapeutic agent in breast, lung, and ovarian cancer is being reviewed. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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17 pages, 1056 KiB  
Review
Application of Nanoparticles for Targeting G Protein-Coupled Receptors
by Xin Ma, Yunfang Xiong and Leo Tsz On Lee
Int. J. Mol. Sci. 2018, 19(7), 2006; https://doi.org/10.3390/ijms19072006 - 10 Jul 2018
Cited by 25 | Viewed by 5100
Abstract
Nanoparticles (NPs) have attracted unequivocal attention in recent years due to their potential applications in therapeutics, bio-imaging and material sciences. For drug delivery, NP-based carrier systems offer several advantages over conventional methods. When conjugated with ligands and drugs (or other therapeutic molecules), administrated [...] Read more.
Nanoparticles (NPs) have attracted unequivocal attention in recent years due to their potential applications in therapeutics, bio-imaging and material sciences. For drug delivery, NP-based carrier systems offer several advantages over conventional methods. When conjugated with ligands and drugs (or other therapeutic molecules), administrated NPs are able to deliver cargo to targeted sites through ligand-receptor recognition. Such targeted delivery is especially important in cancer therapy. Through this targeted cancer nanotherapy, cancer cells are killed with higher specificity, while the healthy cells are spared. Furthermore, NP drug delivery leads to improved drug load, enhanced drug solubility and stability, and controlled drug release. G protein-coupled receptors (GPCRs) are a superfamily of cell transmembrane receptors. They regulate a plethora of physiological processes through ligand-receptor-binding-induced signaling transduction. With recent evidence unveiling their roles in cancer, GPCR agonists and antagonists have quickly become new targets in cancer therapy. This review focuses on the application of some notable nanomaterials, such as dendrimers, quantum dots, gold nanoparticles, and magnetic nanoparticles, in GPCR-related cancers. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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24 pages, 1638 KiB  
Review
GPCRs in Cancer: Protease-Activated Receptors, Endocytic Adaptors and Signaling
by Aleena K. S. Arakaki, Wen-An Pan and JoAnn Trejo
Int. J. Mol. Sci. 2018, 19(7), 1886; https://doi.org/10.3390/ijms19071886 - 27 Jun 2018
Cited by 66 | Viewed by 8751
Abstract
G protein-coupled receptors (GPCRs) are a large diverse family of cell surface signaling receptors implicated in various types of cancers. Several studies indicate that GPCRs control many aspects of cancer progression including tumor growth, invasion, migration, survival and metastasis. While it is known [...] Read more.
G protein-coupled receptors (GPCRs) are a large diverse family of cell surface signaling receptors implicated in various types of cancers. Several studies indicate that GPCRs control many aspects of cancer progression including tumor growth, invasion, migration, survival and metastasis. While it is known that GPCR activity can be altered in cancer through aberrant overexpression, gain-of-function activating mutations, and increased production and secretion of agonists, the precise mechanisms of how GPCRs contribute to cancer progression remains elusive. Protease-activated receptors (PARs) are a unique class of GPCRs implicated in cancer. PARs are a subfamily of GPCRs comprised of four members that are irreversibly activated by proteolytic cleavage induced by various proteases generated in the tumor microenvironment. Given the unusual proteolytic irreversible activation of PARs, expression of receptors at the cell surface is a key feature that influences signaling responses and is exquisitely controlled by endocytic adaptor proteins. Here, we discuss new survey data from the Cancer Genome Atlas and the Genotype-Tissue Expression projects analysis of expression of all PAR family member expression in human tumor samples as well as the role and function of the endocytic sorting machinery that controls PAR expression and signaling of PARs in normal cells and in cancer. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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18 pages, 943 KiB  
Review
Frizzled Receptors as Potential Therapeutic Targets in Human Cancers
by Chui-Mian Zeng, Zhe Chen and Li Fu
Int. J. Mol. Sci. 2018, 19(5), 1543; https://doi.org/10.3390/ijms19051543 - 22 May 2018
Cited by 82 | Viewed by 11951
Abstract
Frizzled receptors (FZDs) are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs) that serve as receptors for secreted Wingless-type (WNT) ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell [...] Read more.
Frizzled receptors (FZDs) are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs) that serve as receptors for secreted Wingless-type (WNT) ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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20 pages, 15941 KiB  
Review
EP4 as a Therapeutic Target for Aggressive Human Breast Cancer
by Mousumi Majumder, Pinki Nandi, Ahmed Omar, Kingsley Chukwunonso Ugwuagbo and Peeyush K. Lala
Int. J. Mol. Sci. 2018, 19(4), 1019; https://doi.org/10.3390/ijms19041019 - 29 Mar 2018
Cited by 56 | Viewed by 14269
Abstract
G-protein-coupled receptors (GPCRs, also called seven-transmembrane or heptahelical receptors) are a superfamily of cell surface receptor proteins that bind to many extracellular ligands and transmit signals to an intracellular guanine nucleotide-binding protein (G-protein). When a ligand binds, the receptor activates the attached G-protein [...] Read more.
G-protein-coupled receptors (GPCRs, also called seven-transmembrane or heptahelical receptors) are a superfamily of cell surface receptor proteins that bind to many extracellular ligands and transmit signals to an intracellular guanine nucleotide-binding protein (G-protein). When a ligand binds, the receptor activates the attached G-protein by causing the exchange of Guanosine-5′-triphosphate (GTP) for guanosine diphosphate (GDP). They play a major role in many physiological functions, as well as in the pathology of many diseases, including cancer progression and metastasis. Only a few GPCR members have been exploited as targets for developing drugs with therapeutic benefit in cancer. Present review briefly summarizes the signaling pathways utilized by the EP (prostaglandin E receptor) family of GPCR, their physiological and pathological roles in carcinogenesis, with special emphasis on the roles of EP4 in breast cancer progression. We make a case for EP4 as a promising newer therapeutic target for treating breast cancer. We show that an aberrant over-expression of cyclooxygenase (COX)-2, which is an inflammation-associated enzyme, occurring in 40–50% of breast cancer patients leads to tumor progression and metastasis due to multiple cellular events resulting from an increased prostaglandin (PG) E2 production in the tumor milieu. They include inactivation of host anti-tumor immune cells, such as Natural Killer (NK) and T cells, increased immuno-suppressor function of tumor-associated macrophages, promotion of tumor cell migration, invasiveness and tumor-associated angiogenesis, due to upregulation of multiple angiogenic factors including Vascular Endothelial Growth Factor (VEGF)-A, increased lymphangiogenesis (due to upregulation of VEGF-C/D), and a stimulation of stem-like cell (SLC) phenotype in cancer cells. All of these events were primarily mediated by activation of the Prostaglandin (PG) E receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all of these events tested with cells in vitro as well as in vivo in syngeneic COX-2 expressing mammary cancer bearing mice or immune-deficient mice bearing COX-2 over-expressing human breast cancer xenografts. We suggest that EP4A can avoid thrombo-embolic side effects of long term use of COX-2 inhibitors by sparing cardio-protective roles of PGI2 via IP receptor activation or PGE2 via EP3 receptor activation. Furthermore, we identified two COX-2/EP4 induced oncogenic and SLC-stimulating microRNAs—miR526b and miR655, one of which (miR655) appears to be a potential blood biomarker in breast cancer patients for monitoring SLC-ablative therapies, such as with EP4A. We suggest that EP4A will likely produce the highest benefit in aggressive breast cancers, such as COX-2 expressing triple-negative breast cancers, when combined with other newer agents, such as inhibitors of programmed cell death (PD)-1 or PD-L1. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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15 pages, 517 KiB  
Review
Deregulation of Frizzled Receptors in Hepatocellular Carcinoma
by Kristy Kwan-Shuen Chan and Regina Cheuk-Lam Lo
Int. J. Mol. Sci. 2018, 19(1), 313; https://doi.org/10.3390/ijms19010313 - 21 Jan 2018
Cited by 17 | Viewed by 8335
Abstract
G protein-coupled receptors (GPCRs) have a substantial role in tumorigenesis and are described as a “cancer driver”. Aberrant expression or activation of GPCRs leads to the deregulation of downstream signaling pathways, thereby promoting cancer progression. In hepatocellular carcinoma (HCC), the Wnt signaling pathway [...] Read more.
G protein-coupled receptors (GPCRs) have a substantial role in tumorigenesis and are described as a “cancer driver”. Aberrant expression or activation of GPCRs leads to the deregulation of downstream signaling pathways, thereby promoting cancer progression. In hepatocellular carcinoma (HCC), the Wnt signaling pathway is frequently activated and it is associated with an aggressive HCC phenotype. Frizzled (FZD) receptors, a family member of GPCRs, are known to mediate Wnt signaling. Accumulating findings have revealed the deregulation of FZD receptors in HCC and their functional roles have been implicated in HCC progression. Given the important role of FZD receptors in HCC, we summarize here the expression pattern of FZD receptors in HCC and their corresponding functional roles during HCC progression. We also further review and highlight the potential targeting of FZD receptors as an alternative therapeutic strategy in HCC. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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890 KiB  
Review
Proteinase-Activated Receptor 2 May Drive Cancer Progression by Facilitating TGF-β Signaling
by Hendrik Ungefroren, David Witte, Bernhard H. Rauch, Utz Settmacher, Hendrik Lehnert, Frank Gieseler and Roland Kaufmann
Int. J. Mol. Sci. 2017, 18(11), 2494; https://doi.org/10.3390/ijms18112494 - 22 Nov 2017
Cited by 17 | Viewed by 8255
Abstract
The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer, it usually acts as a driver of cancer progression in various tumor types by promoting invasion and metastasis in [...] Read more.
The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer, it usually acts as a driver of cancer progression in various tumor types by promoting invasion and metastasis in response to activation by serine proteinases. Recently, we discovered another mode through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor-β (TGF-β) signaling to promote TGF-β1-induced cell migration/invasion and invasion-associated gene expression in ductal pancreatic adenocarcinoma (PDAC) cells. In this chapter, we review what is known about the cellular TGF-β responses and signaling pathways affected by PAR2 expression, the signaling activities of PAR2 required for promoting TGF-β signaling, and the potential molecular mechanism(s) that underlie(s) the TGF-β signaling–promoting effect. Since PAR2 is activated through various serine proteinases and biased agonists, it may couple TGF-β signaling to a diverse range of other physiological processes that may or may not predispose cells to cancer development such as local inflammation, systemic coagulation and pathogen infection. Full article
(This article belongs to the Special Issue Cancer-Driver G Protein-Coupled Receptors as Therapeutic Targets)
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