Carcinoma-specific expression of P2Y11 receptor and its contribution in ATP-induced purinergic signalling and cell migration in human hepatocellular carcinoma cells

Khalid, Madiha; Brisson, Lucie; Tariq, Menahil; Hao, Yunjie; Guibon, Roseline; Fromont, Gaëlle; Mortadza, Sharifah Alawieyah Syed; Mousawi, Fatema; Manzoor, Sobia; Roger, Sébastien; Jiang, Lin‐Hua

doi:10.18632/oncotarget.16191

Cited by 33 publications

(32 citation statements)

References 45 publications

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“…Consistent with our observations, ATP has been reported to induce hepatocellular carcinoma cell migration through P2Y11 . Our results showing that ATP induces migration in deciliated cells and iCCA cells are in line with these data because hepatocellular carcinoma cells, like normal hepatocytes and CCA cells, do not express primary cilia.…”

Section: Discussionsupporting

confidence: 93%

The Chemosensory Function of Primary Cilia Regulates Cholangiocyte Migration, Invasion, and Tumor Growth

et al. 2019

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Cholangiocytes, the epithelial cells lining the biliary tree in the liver, express primary cilia that can detect several kinds of environmental signals and then transmit this information into the cell. We have reported that cilia are significantly reduced in cholangiocarcinoma (CCA) and that the experimental deciliation of normal cells induces a malignant‐like phenotype with increased proliferation, anchorage‐independent growth, invasion, and migration. Here, we tested the hypothesis that the chemosensory function of cholangiocyte primary cilia acts as a mechanism for tumor suppression. We found that in the presence of extracellular nucleotides cilia‐dependent chemosensation of the nucleotides inhibited migration and invasion in normal ciliated cholangiocytes through a P2Y11 receptor and liver kinase B1 (LKB1)–phosphatase and tensin homolog–AKT–dependent mechanism. In contrast, in normal deciliated cholangiocytes and CCA cells, the nucleotides induced the opposite effects, i.e., increased migration and invasion. As activation of LKB1 through a cilia‐dependent mechanism was required for the nucleotide‐mediated inhibitory effects on migration and invasion, we attempted to activate LKB1 directly, independent of ciliary expression, using the compound hesperidin methyl chalcone (HMC). We found that HMC induced activation of LKB1 in both ciliated and deciliated cells in vitro, resulting in the inhibition of migration and proliferation. Furthermore, using a rat syngeneic orthotopic CCA model, we found that HMC inhibited tumor growth in vivo. Conclusion: These findings highlight the importance of the chemosensory function of primary cilia for the control of migration and invasion and suggest that, by directly activating LKB1 and bypassing the need for primary cilia, it is possible to emulate this chemosensory function in CCA cells; these data warrant further studies evaluating the possibility of using HMC as therapy for CCA.

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Section: Discussionsupporting

confidence: 93%

The Chemosensory Function of Primary Cilia Regulates Cholangiocyte Migration, Invasion, and Tumor Growth

et al. 2019

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“…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 ). CD39 KO mice showed an increased incidence of spontaneous and induced hepatocellular carcinoma.…”

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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“…First, we examined the expression level of P2Y11R in human FLS, with HepG2 cancer cells as a positive control . We found that the mRNA and protein expression of P2Y11R in synoviocytes is comparable to that of HepG2 cells (Figure a,b).…”

Section: Resultsmentioning

confidence: 88%

“…13 Treatment with NF340 has been reported to prevent ATP-induced stimulation of cell migration and Ca 2+ signaling in human hepatocellular carcinoma cells. 15 In our study of FLS in RA, we report that P2Y11R is a highly specific inducible factor that responds to cytokine stimulation and we present our evaluation of the effect of P2Y11 receptor antagonism in FLS.…”

Section: Introductionmentioning

confidence: 99%

P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

Gao

2019

IUBMB Life

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Rheumatoid arthritis is a common chronic inflammatory joint disease. Fibroblast‐like synoviocytes‐mediated inflammation is closely associated with the development of rheumatoid arthritis. In this study, we report that P2Y11 receptor activity is required for cytokine‐induced inflammation in primary fibroblast‐like synoviocytes (FLS). P2Y11R is fairly expressed in primary FLS isolated from healthy subjects and is elevated to around three‐ to four‐fold in rheumatoid arthritis‐derived FLS. The expression of P2Y11R is inducible upon IL‐1β treatment. Blockage of P2Y11R by its antagonist suppresses IL‐1β‐induced TNF‐α and IL‐6 induction and ameliorates oxidative stress as determined by levels of cellular ROS and the oxidative byproduct 4‐HNE. Moreover, blockage of P2Y11R by NF340 inhibits IL‐1β‐induced matrix metalloproteinase protein expression as indicated by the levels of MMP‐1, MMP‐3, and MMP‐13. Mechanistically, blockage of P2Y11R mitigates IL‐1β‐activated NFκB signaling, which was revealed by reduced IκBα phosphorylation, nuclear p65 accumulation, and NFκB promoter activity. Our study provides evidence of a protective mechanism of P2Y11R antagonist NF340 against cytokine‐induced inflammation. Therefore, targeting P2Y11R could have potential therapeutic implication in the treatment of RA.

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Carcinoma-specific expression of P2Y11 receptor and its contribution in ATP-induced purinergic signalling and cell migration in human hepatocellular carcinoma cells

Cited by 33 publications

References 45 publications

The Chemosensory Function of Primary Cilia Regulates Cholangiocyte Migration, Invasion, and Tumor Growth

The Chemosensory Function of Primary Cilia Regulates Cholangiocyte Migration, Invasion, and Tumor Growth

Purinergic Signalling: Therapeutic Developments

P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

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