ERK, PKC and PI3K/Akt pathways mediate extracellular ATP and adenosine-induced proliferation of U138-MG human glioma cell line

Objective: Extracellular nucleotides and nucleosides induce proliferation in a set of human glioma cell lines. In this study we investigate the signal transduction pathways involved in ATP and adenosine-mediated proliferation in U138-MG human glioma cells. Methods: Cell proliferation was accessed through [H-3] thymidine incorporation, cell counting and flow cytometry. Protein phosphorylation was detected through Western blotting. Results: ATP or adenosine ( 100 muM) induced extracellular signal-regulated protein kinase (ERK), Akt and GSK3beta phosphorylation. The increase in [H-3] thymidine incorporation induced by ATP or adenosine was decreased when cells were incubated with LY 294002 ( by +/-90%), GF 109203X ( by +/-76%) or PD 098059 ( by +/-63%). The increase in cell numbers with ATP or adenosine was less after a 48-hour treatment of cells with ATP or adenosine plus GF 109203X ( by +/-66%) or LY 294002 ( by +/-83%). Percentage of cells in S phase was decreased in cells treated with LY 294002 plus ATP when compared to ATP-treated cells. Conclusion: Stimulation of purinergic receptors in U138-MG cells leads to cell proliferation mediated by PI3K/Akt, ERK and PKC signaling. It may be clinically important for pharmacological intervention in gliomas to associate purinergic receptor antagonists and signal transduction pathways blockers. Copyright (C) 2004 S. Karger AG, Basel.