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

Hanxing Wan; Rui Xie; Jiangyu Xu; Jialin He; Bo Tang; Qingqing Liu; Sumin Wang; Yanjun Guo; Xin Yang; Tobias Xiao Dong; John M Carethers; Shiming Yang; Hui Dong

doi:10.1038/s41598-017-02562-x

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

Sci Rep. 2017 May 26;7(1):2459. doi: 10.1038/s41598-017-02562-x.

Authors

Hanxing Wan¹, Rui Xie¹, Jiangyu Xu², Jialin He¹, Bo Tang¹, Qingqing Liu¹, Sumin Wang¹, Yanjun Guo¹, Xin Yang¹, Tobias Xiao Dong³, John M Carethers⁴, Shiming Yang⁵, Hui Dong^{6

7}

Affiliations

¹ Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
² Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi, China.
³ Department of Medicine, University of California, San Diego, California, USA.
⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China. [email protected].
⁶ Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China. [email protected].
⁷ Department of Medicine, University of California, San Diego, California, USA. [email protected].

Abstract

Although purinegic signaling is important in regulating gastric physiological functions, it is currently unknown for its role in gastric cancer (GC). We demonstrate for the first time that the expression of P2Y6 receptors was markedly down-regulated in human GC cells and primary GC tissues compared to normal tissues, while the expression of P2Y2 and P2Y4 receptors was up-regulated in GC cells. Moreover, the expression levels of P2Y6 receptors in GC tissues were correlated to tumor size, differentiation, metastasis to lymph nodes, and the survival rate of the patients with GC. Ncleotides activated P2Y6 receptors to raise cytosolic Ca²⁺ concentrations in GC cells through store-operated calcium entry (SOCE), and then mediated Ca²⁺-dependent inhibition of β-catenin and proliferation, eventually leading to GC suppression. Furthermore, UTP particularly blocked the G1/S transition of GC cells but did not induce apoptosis. Collectively, we conclude that nucleotides activate P2Y6 receptors to suppress GC growth through a novel SOCE/Ca²⁺/β-catenin-mediated anti-proliferation of GC cells, which is different from the canonical SOCE/Ca²⁺-induced apoptosis in other tumors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Calcium / metabolism
Calcium Channels / genetics*
Calcium Channels / metabolism
Cell Line, Tumor
Cell Proliferation
Epithelial Cells / drug effects
Epithelial Cells / metabolism
Epithelial Cells / pathology
G1 Phase Cell Cycle Checkpoints / drug effects
G1 Phase Cell Cycle Checkpoints / genetics
Gene Expression Regulation, Neoplastic*
Humans
Indoles / pharmacology
Lymphatic Metastasis
Male
Mice
Mice, Nude
Receptors, Purinergic P2 / genetics*
Receptors, Purinergic P2 / metabolism
Receptors, Purinergic P2Y2 / genetics
Receptors, Purinergic P2Y2 / metabolism
Signal Transduction
Spiperone / pharmacology
Stomach Neoplasms / drug therapy*
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology
Survival Analysis
Tumor Burden / drug effects
Uridine Diphosphate / pharmacology
Uridine Triphosphate / pharmacology*
Xenograft Model Antitumor Assays
beta Catenin / genetics*
beta Catenin / metabolism

Substances

Antineoplastic Agents
CTNNB1 protein, human
Calcium Channels
Indoles
Receptors, Purinergic P2
Receptors, Purinergic P2Y2
beta Catenin
purinoceptor P2Y4
purinoceptor P2Y6
Spiperone
Uridine Diphosphate
Calcium
Uridine Triphosphate
cyclopiazonic acid