Positive feedback control of neutral sphingomyelinase activity by ceramide

While ceramide has emerged as a potent signal transducer, inconsistencies in the kinetics of ceramide generation, or its absence, in response to stimuli have led to confusion and skepticism as to its potential role in apoptosis or proliferation. Here we show that in U937 and HL60 myeloid leukemia cells and in normal skin fibroblasts, cell-permeant ceramides can trigger neutral sphingomyelinase activation, sphingomyelin hydrolysis, and endogenous ceramide generation regardless of Bcl2 overexpression. These observations identify neutral sphingomyelinase as a novel target for ceramide and show that this positive feedback mechanism is responsible for signal propagation, as exemplified by mitogen-activated protein kinase activation in daunorubicin-treated cells. This study provides insight into a fundamental process of cell biology. Indeed, such a sustained ceramide-mediated signal throughout the apoptotic process would ensure self-destruction, perhaps by overriding evolutionary conserved primal cell survival mechanisms.