PMID- 31249523 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 10 DP - 2019 TI - Differential Effects of Purinergic Signaling in Gastric Cancer-Derived Cells Through P2Y and P2X Receptors. PG - 612 LID - 10.3389/fphar.2019.00612 [doi] LID - 612 AB - Gastric cancer (GC) is the one of the most prevalent cancers and one of the leading causes of cancer-induced deaths. Previously, we found that the expression of purinergic P2Y(2) receptor (P2Y(2)R) is increased in GC samples as compared to adjacent healthy mucosa taken from GC-diagnosed patients. In this work, we studied in detail purinergic signaling in the gastric adenocarcinoma-derived cell lines: AGS, MKN-45, and MKN-74, and compared them to a nontumoral epithelial cell line: GES-1. In GC-derived cells, we detected the expression of several purinergic receptors, and found important differences as compared to GES-1 cells. Functional studies revealed a strong contribution of P2Y(2)Rs in intracellular calcium increases, elicited by adenosine-triphosphate (ATP), uridine-triphosphate (UTP), and the P2Y(2)R agonist MRS2768. Responses were preserved in the absence of extracellular calcium and inhibited by P2Y(2)R antagonists. In GES-1 cells, ATP and UTP induced similar responses and the combination of P2X and P2Y receptor antagonists was able to block them. Proliferation studies showed that ATP regulates AGS and MKN-74 cells in a biphasic manner, increasing cell proliferation at 10-100 muM, but inhibiting at 300 muM ATP. On the other hand, 1-300 muM UTP, a P2Y(2)R agonist, increased concentration-dependent cell proliferation. The effects of UTP and ATP were prevented by both wide-range and specific purinergic antagonists. In contrast, in GES-1 cells ATP only decreased cell proliferation in a concentration-dependent manner, and UTP had no effect. Notably, the isolated application of purinergic antagonists was sufficient to change the basal proliferation of AGS cells, indicating that nucleotides released by the cells can act as paracrine/autocrine signals. Finally, in tumor-derived biopsies, we found an increase of P2Y(2)R and a decrease in P2X4R expression; however, we found high variability between seven different biopsies and their respective adjacent healthy gastric mucosa. Even so, we found a correlation between the expression levels of P2Y(2)R and P2X4R and survival rates of GC patients. Taken together, these results demonstrate the involvement of different purinergic receptors and signaling in GC, and the pattern of expression changes in tumoral cells, and this change likely directs ATP and nucleotide signaling from antiproliferative effects in healthy tissues to proliferative effects in cancer. FAU - Hevia, Maria Jose AU - Hevia MJ AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. FAU - Castro, Patricio AU - Castro P AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. AD - Departamento de Fisiologia, Facultad de Ciencias Biologicas, Universidad de Concepcion, Concepcion, Chile. FAU - Pinto, Katherine AU - Pinto K AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. FAU - Reyna-Jeldes, Mauricio AU - Reyna-Jeldes M AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. FAU - Rodriguez-Tirado, Felipe AU - Rodriguez-Tirado F AD - Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. FAU - Robles-Planells, Claudia AU - Robles-Planells C AD - Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. FAU - Ramirez-Rivera, Sebastian AU - Ramirez-Rivera S AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. FAU - Madariaga, Juan Andres AU - Madariaga JA AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. AD - Hospital San Pablo, Coquimbo, Chile. FAU - Gutierrez, Felipe AU - Gutierrez F AD - Hospital San Pablo, Coquimbo, Chile. FAU - Lopez, Javier AU - Lopez J AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. AD - Hospital San Pablo, Coquimbo, Chile. FAU - Barra, Marcelo AU - Barra M AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. AD - Hospital San Pablo, Coquimbo, Chile. FAU - De la Fuente-Ortega, Erwin AU - De la Fuente-Ortega E AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. FAU - Bernal, Giuliano AU - Bernal G AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. FAU - Coddou, Claudio AU - Coddou C AD - Departamento de Ciencias Biomedicas, Facultad de Medicina, Universidad Catolica del Norte, Coquimbo, Chile. LA - eng PT - Journal Article DEP - 20190613 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC6584115 OTO - NOTNLM OT - ATP OT - P2X receptor OT - P2Y receptor OT - gastric cancer OT - paracrine action OT - uridine triphosphate (UTP) EDAT- 2019/06/30 06:00 MHDA- 2019/06/30 06:01 PMCR- 2019/06/13 CRDT- 2019/06/29 06:00 PHST- 2019/03/14 00:00 [received] PHST- 2019/05/15 00:00 [accepted] PHST- 2019/06/29 06:00 [entrez] PHST- 2019/06/30 06:00 [pubmed] PHST- 2019/06/30 06:01 [medline] PHST- 2019/06/13 00:00 [pmc-release] AID - 10.3389/fphar.2019.00612 [doi] PST - epublish SO - Front Pharmacol. 2019 Jun 13;10:612. doi: 10.3389/fphar.2019.00612. eCollection 2019.