Sphk1 promotes breast epithelial cell proliferation via NF-κB-p65-mediated cyclin D1 expression.

Lipid metabolism is crucially involved with the promotion of malignant progression and metastasis in various cancers. Growing evidence suggests that many types of cancers express high levels of sphingosine kinase 1 (Sphk1), which is known to mediate cell proliferation We hypothesized that Sphk1/sphingosine-1-phosphate (S1P) signaling contributes to tumor progression. In MCF10A and MCF10A-Sphk1 breast epithelial cells, we used TNF-α to activate the Sphk1/S1P pathway and the measured expression levels of NF-κBp65 and cyclin D1 mRNA and protein in the presence and absence of an NF-κB-p65 inhibitor. Chromatin immunoprecipitation assays were performed to determine whether NF-κB-p65 binds to the cyclin D1 promoter. We found that overexpression of Sphk1 induced NF-κB-p65 activation, increased expression of cyclin D1, shortened the cell division cycle, and thus promoted proliferation of breast epithelial cells. These findings provide insight into the mechanism by which an Sphk1/NF-κB-p65/cyclin D1 signaling pathway mediates cell proliferation.