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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2015; 21(39): 10931-10935
Published online Oct 21, 2015. doi: 10.3748/wjg.v21.i39.10931
Anticancer effect of adenosine on gastric cancer via diverse signaling pathways
Ayako Tsuchiya, Tomoyuki Nishizaki
Ayako Tsuchiya, Tomoyuki Nishizaki, Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan
Author contributions: Tsuchiya A performed experiments; Tsuchiya A and Nishizaki T wrote and reviewed the paper.
Conflict-of-interest statement: The authors have no conflicts of interest to disclose.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Tomoyuki Nishizaki, MD, PhD, Professor, Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. tomoyuki@hyo-med.ac.jp
Telephone: +81-798-456397 Fax: +81-798-456649
Received: April 21, 2015
Peer-review started: April 22, 2015
First decision: June 2, 2015
Revised: June 11, 2015
Accepted: August 25, 2015
Article in press: August 25, 2015
Published online: October 21, 2015
Abstract

Extracellular adenosine induces apoptosis in a variety of cancer cells via intrinsic and extrinsic pathways. In the former pathway, adenosine uptake into cells triggers apoptosis, and in the latter pathway, adenosine receptors mediate apoptosis. Extracellular adenosine also induces apoptosis of gastric cancer cells. Extracellular adenosine is transported into cells through an adenosine transporter and converted to AMP by adenosine kinase. In turn, AMP activates AMP-activated protein kinase (AMPK). AMPK is the factor responsible for caspase-independent apoptosis of GT3-TKB gastric cancer cells. Extracellular adenosine, on the other hand, induces caspase-dependent apoptosis of MKN28 and MKN45 gastric cancer cells by two mechanisms. Firstly, AMP, converted from intracellularly transported adenosine, initiates apoptosis, regardless of AMPK. Secondly, the A3 adenosine receptor, linked to Gi/Gq proteins, mediates apoptosis by activating the Gq protein effector, phospholipase Cγ, to produce inositol 1,4,5-trisphosphate and diacylglycerol, which activate protein kinase C. Consequently, the mechanisms underlying adenosine-induced apoptosis vary, depending upon gastric cancer cell types. Understand the contribution of each downstream target molecule of adenosine to apoptosis induction may aid the establishment of tailor-made chemotherapy for gastric cancer.

Keywords: Adenosine, Apoptosis, Intrinsic pathway, Extrinsic pathway, Gastric cancer

Core tip: Emerging evidence has pointed to adenosine as a tumor suppressor. The most crucial problem for chemotherapy is side effects. Adenosine is an endogenous substance, and therefore, no or fewer side effects are expected for chemotherapy using adenosine. Extracellular adenosine induces apoptosis of gastric cancer cells through intrinsic and extrinsic signaling pathways. Adenosine and its signaling cascades, therefore, could represent a promising drug for gastric cancer chemotherapy. Moreover, the contribution of each downstream target molecule of adenosine to apoptosis induction may aid the establishment of tailor-made chemotherapy for gastric cancer.