Inhibition of thrombin-stimulated cell proliferation by ceramide is not through inhibition of extracellular signal-regulated protein kinase.

Activation of the thrombin receptor provides a strong mitogenic signal in CCL39 cells. Ceramide was found to inhibit thrombin-mediated mitogenesis in these cells while dihydroceramide had no effect. Many growth inhibitors exert their effect by inhibiting extracellular signal-regulated kinase (ERK) signaling pathway. However, neither ceramide nor dihydroceramide blocked the thrombin-induced activation of ERK. In contrast, both agents potentiated ERK activity. The expression of c-fos, c-jun and cyclin D1, which are downstream of ERK in the mitogenic pathway were stimulated by thrombin but this stimulation was not affected by ceramide or dihydroceramide. Therefore, the ceramide inhibition of thrombin-stimulated cell growth in CCL39 cells does not appear to be mediated by an effect on the activation of ERK. Furthermore, the data also suggest that the separate effects of ceramide on thrombin-stimulated cell growth and ERK activity are mediated by different mechanisms.