Characterization of Sigma Receptor Mediated Apoptosis in Breast Tumor Cells
Abstract
We have previously reported that sigma-2 receptor activation results in a caspase-independent apoptosis in breast tumors, and also differing temporal patterns of intracellular calcium release. Other researchers have demonstrated involvement of sigma-2 receptors with tumor cell proliferation. We have also shown that sigma-2 receptor agonists can increase intracellular ceramide levels and decrease sphingomyelin. Sphingosylphosphorylcholine (SPC) and other sphingoid bases have been similarly shown to regulate diverse cellular functions including cell proliferation, release of calcium from intracellular stores, and apoptotic cell death. We report here that sigma-2 receptor agonist produce dose-dependent increases in sphingosylphosphorylcholine in metastatic breast tumor cell lines (SKBr3, MCF-7/Adr-), with a peak affect occurring at 15 minutes. This effect is antagonized by the sigma-2 receptor antagonist AC-927. In detergent extracts of tumor cells (1% Trition X-lOO, CHAPS 7 mM), structurally-diverse sigma-2 receptor agonists increase the hydrolysis of sphingomyelin to SPC in a concentration dependent manner. This deacylation of sphingomyelin is catalyzed by the enzyme Sphingolipid Ceramide N-deacylase (SCDase). SCDase can also acylate sphingosine to produce ceramide. In a detergent extract of breast tumor cells, sigma-2 receptor agonists increase the acylation of sphingosine to ceramide in a concentration-dependent fashion. These findings suggest that the effects of sigma-2 receptor activation may be mediated by SPC. Furthermore, the ability of sigma-2 receptor agonists to modulate both the deacylation of sphingomyelin to SPC, and acylation of sphingosine to ceramide, in a cell free system provides evidence for the direct receptor modulation of SCDase.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2001
- Accession Number
- ADA407327
Entities
People
- Keith W. Crawford
Organizations
- Howard University