The Role of Sphingosine Kinase 2 in Apoptosis of Human Breast Cancer
Abstract
The sphingolipid metabolite sphingosine-1-phosphate (S1P) is the ligand for a family of five specific G protein-coupled receptors (S1P sub 1-5) that regulate a wide variety of important cellular functions, including growth, survival, 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. In contrast, expression of SphK2 inhibits growth and enhances apoptosis independently of SlP receptor activation. We investigated the role of SphK2 in apoptosis of human breast carcinoma MCF7 cells in response to the DNA damaging agent dioxopurine. Expression of SphK2, which is predominantly localized to the nucleus of MCF7 cells, enhanced apoptosis induced by doxorubicin. Expression of SphK2 also significantly increased beta-galactosidase activity, a marker of senescence. However, in contrast to doxorubicin which WAF1 increases the cyclin-dependent kinase inhibitor P21 and p53 levels, SphK2 expression increased p53-independent expression of P21 (WAF1) and hypophosphorylation of the retinoblastoma protein (pRb) . importantly, down-regulation of endogenous SphK2 protected MCF7 cells from doxoruhicin-induced apoptosis and its effects on p21 without affecting p53.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2005
- Accession Number
- ADA437095
Entities
People
- Heidi Sankala
- Sarah Spiegel
Organizations
- Virginia Commonwealth University