Cancer Letters

Cancer Letters

Volume 264, Issue 1, 8 June 2008, Pages 1-10
Cancer Letters

Mini-review
Ceramide-induced cell death in malignant cells

https://doi.org/10.1016/j.canlet.2008.02.020Get rights and content

Abstract

Ceramide has been shown to be capable to trigger apoptosis in almost any cell, including tumor cells. Ceramide is generated by a de novo pathway or by sphingomyelinases. Sphingomyelinases hydrolyze sphingomyelin in biological membranes to release ceramide and they are named acid, neutral and alkaline sphingomyelinase depending on their maximum activity at acid, neutral and alkaline pH values, respectively. Stimuli that trigger a release of ceramide to mediate apoptosis include CD95, TNF-receptor, DR5, γ-irradiation, cytotoxic drugs, UV-light, bacteria, viruses, some forms of developmental death, anti-CD20 and disruption of the cell’s contact with its matrix, to name a few. Here, we will focus on the role of acid sphingomyelinase in malignant tumors, which function in apoptosis is best characterized and documented by genetic models. We will discuss concepts that unify the biological actions of ceramide and describe the role of ceramide in important anti-tumor treatment modalities, such as γ-irradiation and chemotherapy.

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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