Anti-proliferative Effects of Nucleotides on Gastric Cancer via a Novel P2Y6/SOCE/Ca2+/β-catenin Pathway

Wan, Hanxing; Xie, Rui; Xu, Jiangyu; He, Jialin; Tang, Bo; Liu, Qingqing; Wang, Sumin; Guo, Yanjun; Yang, Xinquan; Dong, Tobias Xiao; Carethers, John M.; Yang, Shi‐Ming; Dong, Hui

doi:10.1038/s41598-017-02562-x

Cited by 37 publications

(26 citation statements)

References 47 publications

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“…Surprisingly and contrary to CRC and PDAC, P2Y 6 activation in gastric cancer triggered an antiproliferative response through the SOCE/Ca 2+ /β-catenin pathway [55]. W h i l e P 2 R Y 2 m R N A a n d P 2 Y 4 p r o t e i n w e r e overexpressed in GC patients and GC cell lines MKN-45 and SGC-7901, both mRNA and P2Y 6 protein levels were down-regulated.…”

Section: P2y 6 Receptor Promotes Pancreatic and Colorectal Cancer Tummentioning

confidence: 86%

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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Section: P2y 6 Receptor Promotes Pancreatic and Colorectal Cancer Tummentioning

confidence: 86%

Reviewing the role of P2Y receptors in specific gastrointestinal cancers

Dagenais-Bellefeuille

Molle

Gendron

2019

Purinergic Signalling

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“…The serosal solution contained the following: 140-mM Na + , 5.4-mM K + , 1.2-mM Ca 2+ , 1. 2.4 | Measurement of [Ca 2+ ] cyt by digital Ca 2+ imaging Ca 2+ imaging experiments were performed as previously described (Wan et al, 2017). Cells grown on coverslips were loaded with 5-μM Fura-2/AM in physiological salt solution, described below, at room temperature (∼22°C) for 50 min and then washed for 30 min.…”

Section: Ussing Chamber Experimentsmentioning

confidence: 99%

Molecular mechanisms of caffeine‐mediated intestinal epithelial ion transports

Zhang

Wan

Yang

et al. 2019

British J Pharmacology

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Background and Purpose: As little is known about the effect of caffeine, one of the most widely consumed substances worldwide, on intestinal function, we aimed to study its action on intestinal anion secretion and the underlying molecular mechanisms. Experimental Approach: Anion secretion and channel expression were examined in mouse duodenal epithelium by Ussing chambers and immunocytochemistry. Ca 2+ imaging was also performed in intestinal epithelial cells (IECs). Key Results: Caffeine (10 mM) markedly increased mouse duodenal short-circuit current (I sc), which was attenuated by a removal of either Cl − or HCO 3 − , Ca 2+-free serosal solutions and selective blockers of store-operated Ca 2+ channels (SOC/Ca 2+ release-activated Ca 2+ channels), and knockdown of Orai1 channels on the serosal side of duodenal tissues. Caffeine induced SOC entry in IEC, which was inhibited by ruthenium red and selective blockers of SOC. Caffeine-stimulated duodenal I sc was inhibited by the endoplasmic reticulum Ca 2+ chelator (N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine), selective blockers (ruthenium red and dantrolene) of ryanodine receptors (RyR), and of Ca 2+-activated Cl − channels (niflumic acid and T16A). There was synergism between cAMP and Ca 2+ signalling, in which cAMP/PKA promoted caffeine/Ca 2+-mediated anion secretion. Expression of STIM1 and Orai1 was detected in mouse duodenal mucosa and human IECs. The Orai1 proteins were primarily colocated with the basolateral marker Na + , K +-ATPase. Conclusions and Implications: Caffeine stimulated intestinal anion secretion mainly through the RyR/Orai1/Ca 2+ signalling pathway. There is synergism between cAMP/PKA and caffeine/Ca 2+-mediated anion secretion. Our findings suggest that a caffeine-mediated RyR/Orai1/Ca 2+ pathway could provide novel potential drug targets to control intestinal anion secretion. 1 | INTRODUCTION Caffeine is a well-known constituent of coffee, cacao, and tea, and one of the most widely consumed substances in the world. In 2014, about 85% of American adults ingested, on average, 164-mg caffeine daily (Mitchell, Knight, Hockenberry, Teplansky, & Hartman, 2014). Caffeine intake induces several physiological effects, including stimulation of nervous and musculoskeletal systems, relaxation of bronchial Abbreviations: [Ca 2+ ]cyt, cytosolic Ca 2+ concentration; 2-APB, 2-aminoethoxydiphenyl borate; CaCC, Ca 2+-activated Cl − channels; CFTR, cystic fibrosis transmembrane conductance regulator; CRAC, Ca 2+ release-activated Ca 2+ channels; DNDS

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“…Furthermore, (S)-methanocarba nucleotides such as 13 are inactive at the P2Y 14 R, and other methanocarba nucleotides have been shown to be inactive at P2Y 12 R and P2Y 13 R (Supporting Information and ref. 53 ).…”

Section: Resultsmentioning

confidence: 99%

“…52 A recent study demonstrated the anti-proliferative effect of P2Y 6 R activation in gastric cancer. 53,29 …”

Section: Discussionmentioning

confidence: 99%

Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y₆ receptor agonists

et al. 2017

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Both agonists and antagonists of the UDP-activated P2Y6 receptor (P2Y6R) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a South-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y6R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4-methoxyimino group on the pyrimidine, but not with a α,β-methylene 5´-diphosphate. (S)-Methanocarba dinucleotide potency was compatible with a N4-methoxy modification on the proximal nucleoside that is assumed to bind at the P2Y6R similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2Y6R binding site prefers a ribose-like group that can attain a (N) conformation, rather than (S). Dinucleotide binding was modeled by homology modeling, docking and molecular dynamics simulations, which suggested the same ribose conformational preferences found empirically.

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Anti-proliferative Effects of Nucleotides on Gastric Cancer via a Novel P2Y6/SOCE/Ca2+/β-catenin Pathway

Cited by 37 publications

References 47 publications

Reviewing the role of P2Y receptors in specific gastrointestinal cancers

Reviewing the role of P2Y receptors in specific gastrointestinal cancers

Molecular mechanisms of caffeine‐mediated intestinal epithelial ion transports

Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y₆ receptor agonists

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Anti-proliferative Effects of Nucleotides on Gastric Cancer via a Novel P2Y6/SOCE/Ca2+/β-catenin Pathway

Cited by 37 publications

References 47 publications

Reviewing the role of P2Y receptors in specific gastrointestinal cancers

Reviewing the role of P2Y receptors in specific gastrointestinal cancers

Molecular mechanisms of caffeine‐mediated intestinal epithelial ion transports

Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y6 receptor agonists

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Product

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Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y₆ receptor agonists