Sphingolipid-Mediated Apoptosis and Tumor Suppression in Breast Carcinoma

摘要

Ceramide has emerged as an important intracellular regulator of cell growth and viability. In breast carcinoma cells, we find that tumor necrosis factor alpha TNF(alpha) causes prolonged and significant accumulation of ceramide, which precedes cell death. We have investigated the mechanism of ceramide formation and the mechanism of ceramide action. This accumulation of ceramide involves activation of ICE-like proteases which are inhibitable by CrmA. On the other hand, the addition of ceramide to cells results in the induction of apoptosis which is inhibited by Bcl-2 and by inhibitors of the caspase-3-type proteases (DEVD). In further examination of the mechanism of ceramide formation, we have determined that TNF alpha causes activation of neutral sphingomyelinase through a drop in glutathione levels. The addition of GSH to TNF alpha treated cells results in replenishment of glutathione levels, prevention of ceramide formation, and partial inhibition of cell death.