Sphingolipid-Mediated Apoptosis and Tumor Suppression in Breast Carcinoma

Abstract

Ceramide has emerged as an important intracellular regulator of cell growth and viability. In breast carcinoma cells, we find that tumor necrosis factor alpha (TNF(alpha) causes prolonged and significant accumulation of ceramide, which precedes cell death. We have investigated the mechanism of ceramide formation and the mechanism of ceramide action. This accumulation of ceramide involves activation of ICE-like proteases which are inhibitable by CrmA. On the other hand, the addition of ceramide to cells results in the induction of apoptosis which is inhibited by Bcl-2 and by inhibitors of the caspase-3-type proteases (DEVD). In further examination of the mechanism of ceramide formation, we have determined that TNF alpha causes activation of neutral sphingomyelinase through a drop in glutathione levels. The addition of GSH to TNF alpha treated cells results in replenishment of glutathione levels, prevention of ceramide formation, and partial inhibition of cell death.

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Document Details

Document Type
Technical Report
Publication Date
Oct 01, 1998
Accession Number
ADA363444

Entities

People

  • Yusuf A. Hannun

Organizations

  • Duke University Hospital

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Alcohols
  • Apoptosis
  • Azo Compounds
  • Breast Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Chemistry
  • Fungi
  • Inhibition
  • Inhibitors
  • Lipids
  • Medical Personnel
  • Neoplasms
  • Peptides
  • Proteins
  • Tumor Cell Line

Readers

  • Cellular and Molecular Pathways of Apoptosis.
  • Molecular Biology and Genetics