Abstract
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 P2Y2 receptor (P2Y2R) 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 P2Y2Rs in intracellular calcium increases, elicited by adenosine-triphosphate (ATP), uridine-triphosphate (UTP), and the P2Y2R agonist MRS2768. Responses were preserved in the absence of extracellular calcium and inhibited by P2Y2R 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 μM, but inhibiting at 300 μM ATP. On the other hand, 1–300 μM UTP, a P2Y2R 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 P2Y2R 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 P2Y2R 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.
Highlights
Cancer, or malignant tumors, comprises a group of diseases that involve abnormal cell growth and proliferation and is a leading cause of death worldwide
We found that both cell lines express several purinergic receptors; with the most remarkable difference being that GES-1 cells express more P2X receptors subtypes than AGS cells, which in general express more P2Y receptors (Figure 1A)
The expression varies among the cell lines, we find that healthy mucosa-derived GES-1 expresses more P2XRs as compared to Gastric cancer (GC)-derived cells
Summary
Malignant tumors, comprises a group of diseases that involve abnormal cell growth and proliferation and is a leading cause of death worldwide. Several factors can trigger the development and spread of malignant tumors, including tobacco use, obesity, alcohol consumption, infectious pathogens, exposure to ionizing radiation, and genetic factors, resulting in a complex pathophysiology and treatment. This pathology can be developed in various tissues and cell types, and among these, gastric cancer (GC) is the leading cause of cancer-induced deaths in Chile with an estimated mortality of 20/100,000 inhabitants (25.1/100,000 males and 13.2/100,000 females) for the last 10 years (Heise et al, 2009). It is desirable to develop therapeutic strategies to treat GC, as well as techniques that can predict risk of disease
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.