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Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells

Item Type:Article
Title:Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells
Creators Name:von Haefen, C. and Wieder, T. and Gillissen, B. and Staerck, L. and Graupner, V. and Doerken, B. and Daniel, P.T.
Abstract:The intracellular pathways leading to mitochondrial activation and subsequent cell death in the ceramide-mediated stress response have been intensively studied in recent years. Experimental evidence has been provided that ceramide-induced apoptosis is inhibited by overexpression of antiapoptotic proteins of the Bcl-2 family. However, the direct effect of proapoptotic gene products, e.g. Bax, on ceramide-induced death signalling has not yet been studied in detail. In the present work, we show by measurement of mitochondrial permeability transition, cytochrome c release, activation of caspase-3 and DNA fragmentation that ceramide-induced apoptosis is marginal in Bax-negative DU 145 cells. Reconstitution of Bax by generation of DU 145 cells stably expressing this proapoptotic factor, clearly enhanced ceramide-induced apoptosis at all levels of the mitochondrial signalling cascade. Using the broad-range caspase inhibitor zVAD-fmk and zDEVD-fmk, an inhibitor of caspase-3-like activities, we demonstrate that the ceramide-induced mitochondrial activation in Bax-transfected DU 145 cells is caspase-independent. On the other hand, apoptotic events located downstream of the mitochondria, e.g. DNA fragmentation, were shown to be caspase-dependent. This influence of Bax on ceramide-induced apoptosis was confirmed in another cellular system: whereas Bax-positive HCT116 wild type cells were very sensitive towards induction of cell death by C2-ceramide, sensitivity of Bax knock-out HCT116 cells was significantly reduced. Thus, we conclude that Bax is a key activator of ceramide-mediated death pathways.
Keywords:Proapoptotic Genes, Bax, Ceramide, Mitochondria, DU 145 Cells, HCT116 Cells
Source:Oncogene
ISSN:0950-9232
Publisher:Nature Publishing Group (U.K.)
Volume:21
Number:25
Page Range:4009-4019
Date:6 June 2002
Official Publication:https://doi.org/10.1038/sj.onc.1205497
PubMed:View item in PubMed

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