Eicosanoid production by the human gastric cancer cell line AGS and its relation to cell growth

Eicosanoids have the ability to stimulate or inhibit the proliferation of epithelial cells, and they have been shown to modulate the growth characteristics of certain tumor cell lines. In addition, many epithelial cells have the ability to produce eicosanoids, which may then serve as autocrine growth factors. We have measured the eicosanoids produced by the human stomach cell line AGS using reverse-phase high-performance liquid chromatography. AGS cells were incubated with [3H]arachidonic acid and stimulated to release eicosanoids by the calcium ionophore A23187. Unlike its counterpart from the normal stomach, the AGS tumor cell line produced prominent amounts of the leukotrienes D4, C4, and B4; 6-keto-prostaglandin F1 alpha; thromboxane B2; hydroxyeicosatetraenoic acids; and smaller amounts of other prostaglandins in response to A23187. Under basal condition (in the absence of calcium ionophore), hydroxyeicosatetraenoic acid was produced in greatest relative amount compared with the other eicosanoids. To elucidate the potential autacoid role of these agents, exogenous eicosanoids were added to AGS cells, and proliferation was measured. Prostaglandins D2 and E2 suppressed the growth of AGS cells in a dose-dependent manner. On the other hand, leukotrienes D4 and C4 had a dose-dependent proliferative effect on cell growth. The lipoxygenase inhibitor nordihydroguaiaretic acid (10(-6), 10(-5) M) and hydrocortisone (10(-5) M) had dose-dependent suppressive effects on growth, whereas indomethacin (10(-6) M and 10(-5) M) had no effect. These results suggest that AGS cells preferentially metabolize arachidonic acid through the 5-lipoxygenase pathway, which results in the production of growth-stimulatory autocoids. Agents that selectively block this arm of eicosanoid metabolism might be useful therapeutic agents in the treatment of certain gastrointestinal cancers.