CERAMIDE SYNTHASE MEDIATES DAUNORUBICIN-INDUCED APOPTOSIS - AN ALTERNATIVE MECHANISM FOR GENERATING DEATH SIGNALS

The sphingomyelin pathway, which is initiated by sphingomyelin hydroly sis to generate the second messenger ceramide, signals apoptosis for t u mor necrosis factor alpha, Fas, and ionizing radiation. In the prese nt studies, the anticancer drug daunorubicin also stimulated ceramide elevation and apoptosis in P388 and U937 cells, Cell-permeable analogs of ceramide, but not other lipid second messengers, mimicked daunorub icin in inducing apoptosis. Daunorubicin-stimulated ceramide elevation , however, did not result from sphingomyelin hydrolysis, but rather fr om de novo synthesis via activation of the enzyme ceramide synthase. A n obligatory role for ceramide synthase was defined, since its natural specific inhibitor, fumonisin B1, blocked daunorubicin-induced cerami de elevation and apoptosis. These studies demonstrate that ceramide sy nthase activity can be regulated in eukaryotes and constitute definiti ve evidence for a requirement for ceramide elevation in the induction of apoptosis.