The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

Abstract

The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and gamma -irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber disease and control fibroblasts. Interestingly, Farber disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis

Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo

“…Although our data are in agreement with previous findings using B13 (Selzner et al, 2001;Ogretmen and Hannun, 2004) or NOE (Hara et al, 2004) to block CDases, it has been reported that primary human SV-40 transformed skin fibroblasts or lymphocytes from Farber disease patients, a genetic disorder characterized by a decrease in acid CDase, were as sensitive to DNRinduced cell death as cells from healthy controls (Burek et al, 2001). This reported discrepancy with our findings might well be owing to the tumor specificity or type of cells used.…”

Mitochondrial Cytochrome c Release Mediates Ceramide-induced Activator Protein 2 Activation and Gene Expression in Keratinocytes

“…Accordingly, sensitivity toward ceramide-induced apoptosis was recently reported to differ between different cell types. In these studies, similar to our observation, tumor cells glare to be more sensitive toward ceramide-induced apoptosis as compared with primary cells (57,58).…”

Ceramide catabolism critically controls survival of human dendritic cells

“…In fact, the overexpression of acid ceramidase protects fibroblasts from tumor necrosis factor (TNF)-induced ceramide accumulation and cell death [20], and the fibroblasts of Farber's disease patients, which have an inherited deficiency in acidic ceramidase, are more sensitive to ceramide-induced cell death [29]. The role of sphingosine kinases in cell survival and transformation has been investigated extensively [19,30].…”