Involvement of nuclear factor-κB in endothelin-A-receptor-induced proliferation and inhibition of apoptosis

Endothelins have been implicated in the regulation of cell proliferation, differentiation, and apoptosis, but the mechanisms of these complex events are not yet fully understood. Although the nuclear factor-κB (NF-κB) was shown to play a prominent role in the above processes, its participation in endothelin receptor A (ET_AR) signaling has not been previously demonstrated. This study provides evidence that NF-κB is involved in ET_AR-induced proliferation and inhibition of apoptosis. Endothelin (ET)-1, ET-3, and sarafotoxin b induce cell proliferation and prevent apoptosis induced by serum deprivation in a Chinese hamster lung (CCL39) cell line that stably expresses ET_AR (CCL39ET_A). Activation of ET_AR resulted in enhanced DNA-binding activity of NF-κB and degradation of IκB-α. Expression of the dominant negative form of IκB-α (IκBΔN) inhibited the proliferative activities mediated by ET_AR as well as its antiapoptotic activities. Treatment of the cells with prostaglandin A₁, an inhibitor of IκB kinase-β, reduced ET-1-induced proliferation and its antiapoptotic effect. These findings indicate that the regulation of cell proliferation and apoptosis by ET_AR is mediated by the ET_AR-activated NF-κB.