Hormone-activated nuclear receptors inhibit the stimulation of the JNK andERK signalling pathways in endothelial cells

Glucocorticoid hormones, retinoids, and vitamin D3 display anti-angiogenic activity in tumor-bearing animals. However, despite their in vivo effect on the tumor vasculature little is known about their mechanism of action, Her e we show that the synthetic glucocorticoid dexamethasone (Dex) and retinoi c acid (RA) inhibit the activation of c-Jun N-terminal kinase (JNK) and ext racellular-regulated kinase (ERK) signalling pathways by the pro-angiogenic agents tumor necrosis factor and vascular endothelial growth factor in end othelial cells. In contrast, Dex and RA failed to inhibit the activation of the p38 mitogen-activated protein kinase cascade. As a number of pro-angio genic factors activate AP-1 transcription factor via the JNK and ERK pathwa ys, our results suggest that the antagonism with AP-1 mel underlie at least partially the anti-angiogenic effect of glucocorticoids and retinoids, (C) 1999 Federation of European Biochemical Societies.