The Role of Sphingosine Kinase 2 in Apoptosis of Human Breast Cancer Cells
Abstract
The sphingolipid metabolite sphingosine-1-phosphate (S1P) is the ligand for a family of five specific G protein-coupled receptors (S1P1-5)that regulate a wide variety of important cellular functions, including growth, survival, cytoskeletal rearrangements, and cell motility. However, whether it also has an intracellular action is still a matter of debate. S1P is formed by the ATP-dependent phosphorylation of sphingosine catalyzed by types 1 and 2 sphingosine kinase (SphK). Many studies have shown that SphK1 stimulates cell proliferation and protects cells from apoptosis. Recently, we reported that in contrast, expression of SphK2 inhibited growth and enhanced apoptosis independently of S1P receptor activation (1). In this study, we investigated the role of SphK2 in human breast carcinoma MCF7 cells in response to the DNA damaging agent doxorubicin. Down-regulation of endogenous SphK2 in MCF7 cells with siRNA decreased doxorubicin-induced expression of p21 without affecting p53. Exposure of MCF7 breast tumor cells to doxorubicin produces a marked increase in the G2/M and S phase populations and a corresponding decrease in the G0/G1 population. Down regulation of SphK2 resulted in decreased G2/M and S phase populations and an increased G0/G1 population. Our results suggest that SphK2 might be involved in increases in p21WAF1 induced by doxorubicin in a p53- independent manner.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2006
- Accession Number
- ADA455788
Entities
People
- Heidi Sankala
- Sarah Spiegel
Organizations
- Virginia Commonwealth University