Mini-reviewCeramide-induced cell death in malignant cells
Introduction
Death receptors such as CD95, TNF-receptor or DR5 trigger apoptosis of cells via a recruitment and activation of caspases, in particular caspase 8, that results in either a direct stimulation of executor caspases such as caspase 3 or activation of the mitochondrial death receptor pathway, which includes the activation of Bax and Bak, translocation of Bax to the mitochondrial membrane, integration of Bax and Bak into the outer mitochondrial membrane, release of cytochrome c, Smac/Diablo and HtrA2/Omi and activation of the permeability transition pore, association of cytochrome c with APAF1 and dATP and finally activation of caspase 3 and execution of apoptosis (for recent reviews see [1], [2], [3]).
Section snippets
Molecular role of ceramide in apoptosis – biophysical considerations
Ceramide has been shown to be critically involved in this cascade: ceramide is formed in cellular membranes by de novo synthesis via a pathway involving the serine–palmitoyl–CoA transferase or by hydrolysis of sphingomyelin catalyzed by acid, neutral and alkaline sphingomyelinases, which exhibit their peak activity at the respective pH values [4], [5]. Although recent studies also imply the neutral and alkaline sphingomyelinase in the induction of apoptosis [6], [7], most studies investigated
Ceramide-induced signalling molecules
In addition to the change of membrane properties, ceramide was also shown to interact with and activate phospholipase A2 [48], kinase suppressor of Ras (KSR; identical to ceramide-activated protein kinase) [49], ceramide-activated protein serine–threonine phosphatases [50], protein kinase C isoforms [51] and c-Raf-1 [52]. Furthermore, ceramide was shown to inhibit the potassium channel Kv1.3 and calcium release activated calcium (CRAC) channels [53], [54], [55]. Functional inhibition of Kv1.3
Ceramide in death receptor-induced apoptosis
Studies from our laboratory demonstrated that the death receptors CD95 and DR5 activate the acid sphingomyelinase and trigger the translocation of the enzyme onto the extracellular leaflet of the cell membrane [8], [10]. Electron microscopy studies suggested that the acid sphingomyelinase localizes to intracellular vesicles that are mobilized upon receptor stimulation, fuse with the cell membrane and expose the acid sphingomyelinase on the outer leaflet of the cell membrane [8], [10] (Fig. 2).
Ceramide in radiation-induced apoptosis
The acid sphingomyelinase and ceramide were shown to be critically involved in the response of cells to γ-irradiation [21], [22], [69], [70], [71], [72], [73], which is highly relevant for tumor therapy. The groups from Kolesnick, Fuks and Haimovitz-Friedman demonstrated an activation of the acid sphingomyelinase and a release of ceramide in a variety of cells upon γ-irradiation [21], [22], [69], [70], [71], [72], [73]. Cells deficient for the acid sphingomyelinase were resistant to
Ceramide in UV-light-mediated apoptosis
Several recent studies demonstrated a critical role of ceramide for UV-light induced apoptosis. UV-A and UV-C light activate the acid sphingomyelinase and trigger the release of ceramide [23], [24], [25], [26], while cells deficient for acid sphingomyelinase fail to release ceramide and to undergo apoptosis upon UV-light radiation. Recent studies also demonstrated that UV-light triggers the formation of large ceramide-enriched membrane domains in the cell membrane, which are critical for the
Ceramide and chemotherapy
Much less is known about the role of endogenous ceramide in chemotherapy and chemotherapy-induced cell death. Initial studies demonstrated that doxorubicin-induced death of oocytes requires expression of the acid sphingomyelinase and release of ceramide [27]. Oocytes derived from acid sphingomyelinase-deficient mice were resistant to doxorubicin. Further studies from Dimanche-Boitrel and co-workers revealed an activation of the acid sphingomyelinase and a release of ceramide upon treatment of
Ceramide in mitochondria and cell death
Several recent studies indicate that ceramide is also present in mitochondria [74], [75], [76], [77], [78], [79]. Mitochondrial ceramide seems to be generated via the de novo synthesis pathway, a reverse activity of the ceramidase and/or activity of the acid sphingomyelinase, which has been shown to reside in the space between the inner and outer mitochondrial membrane [74], [75], [76], [77], [78]. The acid sphingomyelinase has been demonstrated to associate with procaspase 3 present in the
Short chain ceramides
Several recent studies [82], [83], [84], [85] employed short chain ceramides to kill tumor cells. However, although ceramide analogs efficiently kill tumor cells in vitro, at present no convincing concepts and drugs are available to selectively target tumor cells in vivo. Studies by Ogretmen et al. employed cationic pyridinium-ceramides that seem to accumulate in mitochondria of tumor cells [86], however, the selectivity of these drugs needs to be firmly established.
Summary and perspectives
The last years clearly demonstrated that ceramide is critically involved in many modalities of tumor treatment. Ceramide-enriched membrane platforms provide a model how ceramide can be involved in many stress and pro-apoptotic stimuli. Ceramide-enriched membrane platforms serve to cluster and re-organize receptors and signalling molecules, which results in the amplification of a primary signal and finally apoptosis. Further studies revealed a critical role of ceramide for chemotherapy-,
Acknowledgement
The authors thank S. Moyrer for excellent support.
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