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The Role of Sphingosine Kinase 2 in Apoptosis of Human Breast Cancer Cells
Annual summary rept. 5 Apr 2005-4 Apr 2006
VIRGINIA COMMONWEALTH UNIV RICHMOND
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The sphingolipid metabolite sphingosine-1-phosphate S1P is the ligand for a family of five specific G protein-coupled receptors S1P1-5that 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 G2M and S phase populations and a corresponding decrease in the G0G1 population. Down regulation of SphK2 resulted in decreased G2M and S phase populations and an increased G0G1 population. Our results suggest that SphK2 might be involved in increases in p21WAF1 induced by doxorubicin in a p53- independent manner.
APPROVED FOR PUBLIC RELEASE