Epidermal growth factor protects GH3 cells from adenosine induced growth arrest

We have demonstrated that high doses of adenosine (0.1 mM) inhibit the growth of the rat pituitary GH(3) cell line. This effect was not mediated via cell surface adenosine receptors as the adenosine agonists N(6)-(2-phenylisopropyl)adenosine (PIA, 0.1 mM) and 5'-N- ethylcarboxamidoadenosine (NECA, 0.1 mM) were unable to reproduce the growth inhibitory effect of adenosine. The adenosine uptake inhibitor dipyridamole completely blocked the growth inhibitory effect of adenosine suggesting that its site of action is intracellular. Epidermal growth factor (EGF) was able to completely reverse the growth inhibitory effect, restoring the growth rate of cultures treated with adenosine and EGF to that of control cultures. The ratio of cells in G(0)/G(1):S:G(2)/M phases of the cell cycle was unaltered in adenosine treated compared with control cultures suggesting that there was no change in the rate of cell division, however the degree of apoptosis was markedly increased in adenosine treated cultures. EGF was able to reduce the adenosine induced apoptosis almost to levels seen in the control cultures. Thus the mechanism of the growth inhibitory effect of adenosine does not appear to be by reducing the rate of cell division but rather by increasing the rate of cell death and EGF restores the growth rate of adenosine treated cells to that of untreated cells by preventing adenosine induced apoptosis.