Apoptosis induced by intracellular ceramide accumulation in MDA-MB-435 breast carcinoma cells is dependent on the generation of reactive oxygen species

S. Y.Velda Chan, Ashley L. Hilchie, Michael G. Brown, Robert Anderson, David W. Hoskin

Résultat de recherche: Articleexamen par les pairs

25 Citations (Scopus)

Résumé

Strategies to promote intracellular ceramide accumulation in cancer cells may have therapeutic utility because ceramide is an important second messenger during apoptosis. Exposure to cell-permeable C6 ceramide or tricyclodecan-9-yl-xanthate (an inducer of de novo ceramide synthesis and an inhibitor of sphingomyelin synthase) caused MDA-MB-435 human breast carcinoma cells to die by apoptosis. Concomitant treatment with the ceramidase inhibitor d-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (MAPP) or the glucosylceramide synthase inhibitor 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) potentiated the cytotoxic effect of C6 ceramide, indicating that C6 ceramide-mediated cytotoxicity was antagonized by the action of ceramidases and glucosylceramide synthase. Interestingly, treatment with PPMP alone, but not MAPP alone, also induced apoptosis in MDA-MB-435 cells, suggesting that conversion to glucosylceramide rather than catabolism by ceramidases prevented endogenous ceramide from reaching cytotoxic levels. C6 ceramide-induced apoptosis in MDA-MB-435 cells was associated with the generation of reactive oxygen species, and was inhibited by the antioxidants N-acetylcysteine and glutathione. Although mitochondrial membrane integrity was disrupted in C6 ceramide-treated MDA-MB-435 cells, apoptosis was not mediated by caspases because there was no protective effect by the pan-caspase inhibitor z-VAD-fmk. Collectively, these findings indicate that strategies to enhance intracellular ceramide accumulation in malignant cells might offer a novel approach to the treatment of breast cancer.

Langue d'origineEnglish
Pages (de-à)1-11
Nombre de pages11
JournalExperimental and Molecular Pathology
Volume82
Numéro de publication1
DOI
Statut de publicationPublished - févr. 2007

Note bibliographique

Funding Information:
This work was supported by grants to D. Hoskin from the Dairy Farmers of Canada and the Natural Sciences and Engineering Research Council of Canada. V. Chan was supported by a Cancer Research Training Program Award with funding from the Dalhousie Cancer Research Program.

ASJC Scopus Subject Areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Clinical Biochemistry

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