Regulation of Cell Survival and Motility in Human Breast Cancer Cells by Sphingosine Kinase
Abstract
The sphingolipid metabolite, sphingosine-1-phosphate (S1P) formed by phosphorylation of sphingosine, has been implicated in cell growth, suppression of apoptosis, and angiogenesis. We have examined where increased intracellular S1P produced by overexpression of sphingosine kinase contributes to tumorigenesis of breast adenocarcinoma MCF-7 cells. Sphingosine kinase type 1 (SPHK1) blocks MCF-7 cell death induced by anti-cancer drugs, sphingosine and TNF-alpha. The cytoprotectie effect of SPHK1 was reversed by N,N'-dimethylsphingosine, a specific inhibitor of SPHKs. Enforced expression of SPHK1 in MCF-7 cells also conferred a growth advantage as determined by proliferation and growth in soft agar. Although no changes in estrogen receptor levels could be detected, estrogen antagonists eliminated this growth advantage. EDG-1 is a GPCR for S1P that mediates S1P-directed cell migration and vascular maturation. Cell migration toward PDGF, which stimulates sphingosine kinase and increases S1P levels, was dependent on expression of S1P1/EDG-1, and conversely, deletion of S1P1/EDG-1, inhibition of sphingosine kinase of treatment with pertussis toxin to uncouple Gi-linked receptors suppressed chemotaxis toward PDGF. PDGF indusced tykrosine phosphorylation of focal adhesion proteins, including FAK and Src whereas tyrosine phosphorylation of the PDGFR and ERK activation was unaltered.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2002
- Accession Number
- ADB282576
Entities
People
- John P. Hobson
- Sarah Spiegel
Organizations
- United States Army Medical Research and Development Command