Published online Oct 21, 2015. doi: 10.3748/wjg.v21.i39.10931
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
Processing time: 180 Days and 20.1 Hours
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.
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.