Upregulation of P2Y2 nucleotide receptor in human hepatocellular carcinoma cells

Tak, Eunyoung; Jun, Dae Young; Kim, Seok Hwan; Park, Gil‐Chun; Lee, Jooyoung; Hwang, Shin; Song, Gi‐Won; Lee, Sung‐Gyu

doi:10.1177/0300060516662135

Cited by 20 publications

(19 citation statements)

References 50 publications

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“…ATP increases calcium uptake by rat hepatoma cells, probably via P2Y 2 or P2Y 4 R subtypes. There is upregulation of P2Y 2 R in human hepatocellular carcinoma cells ( Tak et al, 2016 ), which mediates proliferation and migration of the cells ( Xie et al, 2014 ). Carcinoma-specific expression of P2Y 11 R make a major contribution to ATP-induced signalling that controls cell migration in human hepatocellular carcinoma cells ( Khalid et al, 2017 ).…”

Section: Diseases Of the Livermentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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Section: Diseases Of the Livermentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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“…This hypoxic environment positively alters cancer cell metabolism to favor cell survival while contributing to aberrant tumor vascularization and increasing metastatic potential [42]. One way that cancer cells trigger these survival responses is via the expression of the transcription factor hypoxia-induced factor 1-alpha (HIF-1α), as observed in multiple HCC cell lines [42,43]. In this context, the up-regulation of HIF-1α expression in response to hypoxic conditions resulted in an increase of P2Y 2 protein expression in normal hepatocyte cell line HepaRG and in cancerous HepG2 cells [43].…”

Section: P2y 2 Receptor Activation Contributes To Cell Dissemination mentioning

confidence: 99%

Reviewing the role of P2Y receptors in specific gastrointestinal cancers

Dagenais-Bellefeuille

Molle

Gendron

2019

Purinergic Signalling

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Extracellular nucleotides are important intercellular signaling molecules that were found enriched in the tumor microenvironment. In fact, interfering with G protein-coupled P2Y receptor signaling has emerged as a promising therapeutic alternative to treat aggressive and difficult-to-manage cancers such as those affecting the gastrointestinal system. In this review, we will discuss the functions of P2Y receptors in gastrointestinal cancers with an emphasis on colorectal, hepatic, and pancreatic cancers. We will show that P2Y 2 receptor up-regulation increases cancer cell proliferation, tumor growth, and metastasis in almost all studied gastrointestinal cancers. In contrast, we will present P2Y 6 receptor as having opposing roles in colorectal cancer vs. gastric cancer. In colorectal cancer, the P2Y 6 receptor induces carcinogenesis by inhibiting apoptosis, whereas P2Y 6 suppresses gastric cancer tumor growth by reducing β-catenin transcriptional activity. The contribution of the P2Y 11 receptor in the migration of liver and pancreatic cancer cells will be compared to its normal inhibitory function on this cellular process in ciliated cholangiocytes. Hence, we will demonstrate that the selective inhibition of the P2Y 12 receptor activity in platelets was associated to a reduction in the risk of developing colorectal cancer and metastasis formation. We will succinctly review the role of P2Y 1 , P2Y 4 , P2Y 13 , and P2Y 14 receptors as the knowledge for these receptors in gastrointestinal cancers is sparse. Finally, redundant ligand selectivity, nucleotide high lability, cell context, and antibody reliability will be presented as the main difficulties in defining P2Y receptor functions in gastrointestinal cancers.

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“…P2Y2R is widely expressed in hepatocytes [28]; its activation promotes cellular survival during an inflammatory process associated with acute liver damage [16] and is required for cell cycle progression through the expression of cyclins and other essential elements for efficient hepatocyte proliferation [4]. Furthermore, several findings have associated P2Y2R with proliferative and survival processes, such as partial hepatectomy [29] and hypoxic challenge [30,31], in animal models of liver growth. Supporting our findings, in a model of carcinogenesis-induction by DEN injection, it was recently described that in a P2YR2 -/genetic background, DEN induced a smaller number of tumors and favored an early proliferative response upon toxic administration, indicating that cellular proliferation in response to liver injury, dependent on P2Y2R, is relevant to the liver disease progression [8].…”

Section: Discussionmentioning

confidence: 99%

Increased Purinergic Responses Dependent on P2Y2 Receptors in Hepatocytes from CCl4-Treated Fibrotic Mice

Velázquez‐Miranda

Molina-Aguilar

González‐Gallardo

et al. 2020

IJMS

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Inflammatory and wound healing responses take place during liver damage, primarily in the parenchymal tissue. It is known that cellular injury elicits an activation of the purinergic signaling, mainly by the P2X7 receptor; however, the role of P2Y receptors in the onset of liver pathology such as fibrosis has not been explored. Hence, we used mice treated with the hepatotoxin CCl4 to implement a reversible model of liver fibrosis to evaluate the expression and function of the P2Y2 receptor (P2Y2R). Fibrotic livers showed an enhanced expression of P2Y2R that eliminated its zonal distribution. Hepatocytes from CCl4-treated mice showed an exacerbated ERK-phosphorylated response to the P2Y2R-specific agonist, UTP. Cell proliferation was also enhanced in the fibrotic livers. Hepatic transcriptional analysis by microarrays, upon CCl4 administration, showed that P2Y2 activation regulated diverse pathways, revealing complex action mechanisms. In conclusion, our data indicate that P2Y2R activation is involved in the onset of the fibrotic damage associated with the reversible phase of the hepatic damage promoted by CCl4.

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Upregulation of P2Y2 nucleotide receptor in human hepatocellular carcinoma cells

Cited by 20 publications

References 50 publications

Purinergic Signalling: Therapeutic Developments

Purinergic Signalling: Therapeutic Developments

Reviewing the role of P2Y receptors in specific gastrointestinal cancers

Increased Purinergic Responses Dependent on P2Y2 Receptors in Hepatocytes from CCl4-Treated Fibrotic Mice

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