| Extracellular purines (adenosine triphosphate (ATP), adenosine 5'-diphosphate (ADP) and adenosine(ADO)) and pyrimidines (uridine 5'- triphosphate (UTP) and UDP ) are important signaling molecules that activate specific transmembrane receptors in most cell types to mediate diverse biological effects. ATP and related compounds are widespread transmitters for extracellular communication in many cell types. By coupling to specific purinergic receptors ATP is involved in a large variety of cellular function. Receptors for purines and pyrimidines (P receptor), first suggested by Burnstock, are divided into two major classes termed adenosine or P1 receptors, at which adenosine is the principal natural ligand, and P2 receptors, at which ATP, ADP, UTP and UDP is the principal natural ligand. To date four P1 receptors subtypes have been identified, A1, A2A, A2B, A3, all coupled to G proteins, with distinct tissue distribution and pharmacological properties. The P2 receptors are divided into two families: the ligand-gated ion channels (P2X) and the G protein-coupled receptors (P2Y). Cloning studies have revealed seven subtypes of P2X receptors, namely P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7, respectively, and several subtypes of P2Y receptors, including P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12 and P2Y13 et al.Extracellular ATP has been reported to exhibit anticancer activity in vivo when injected intraperitoneally into tumor bearing animals. Based on those animal model studies, the first clinical trials with cancer patients have been initiated. Moreover, ATP has been reported to inhibit the growth of many tumor cells in vitro. The molecular basis of both in vivo and in vitro tumor growth inhibition by extracellular ATP is still not clearly understood. A variety of in vitro studies on the effect of extracellular ATP in several transformed and nontransformed cells revealed controversial results. In some cell systems extracellular ATP at low concentrations was mitogenic. In combination with other known mitogens, ATP synergistically displayed growth stimulation. These stimulatory effects of ATP were probably mediated by P2-purinoceptors in the cell membrane which initiate signaling cascades involving the activation of early growth response genes. However, extracellular ATP at higher concentrations displays cytostatic as well as cytotoxic effects in a variety of cell systems, especially tumor cells. This inhibitory effect is considered to be related to the apoptosis. Several other mechanisms of ATP-mediated cytotoxicity have been discussed. Cells of moderate differentiated esophageal cancer Kyse-140 lineage expressed P2Y2 purinoceptors, which mediate the growth inhibition and apoptosis of ATP. Other cells, like fibroblasts, are inhibited by extracellular ATP through the continuous generation of adenosine from ATP via the action of extracellular as well as membrane-bound nucleotidases. It is well known that extracellular ATP can be transformed in AMP by a variety of enzymes that are called ecto-NTPDases ('ecto-nucleoside triphosphate diphosphohydrolase') and finally to adenosine by ecto-nucleotidases. There is growing evidence that adenosine exerts the effects of growth inhibition on many tumor cell types. Therefore, adenosine, the final metabolite in the stepwise dephosphorylation of ATP, may be responsible for the growth inhibition effects of ATP. Adenosine has been reported to induce morphologically and biochemically typical apoptosis in various cells. It was shown to elicit its effects on cell death through adenosine receptor signaling. Recently, Lewis et al reported that adenosine toxicity might not always involve cell-surface receptors, and the nucleoside transport across cell membrane may be involved in its mechanism. However, the effects of ATP and adenosine on human poorly differentiated esophageal and stomach cancer cells, as well as their molecular mechanism have not been reported. To investigate the effects of ATP and adenosine on human poorly differentiated esophageal cancer TE-13 cells, and...
|
PDF Full Text Request