Sphingosine kinase (SphK) 1 and SphK2 play equivalent roles in mediating insulin's mitogenic action.

Insulin, an established mitogen that promotes breast cancer cell growth, has been implicated in the link between obesity and an increased risk of breast cancer. However, the current understanding of signaling pathways that mediate the mitogenic action of insulin remains incomplete. Here we provide the first evidence that insulin is capable of activating both sphingosine kinase (SphK) 1 and SphK 2, two isoenzymes that often exhibit opposing effects in the regulation of cell survival and growth. Insulin stimulates the phosphorylation of both SphK1 and SphK2 in a similar time- and dose-dependent manner. Interestingly, both isoenzymes are responsible equally for insulin-induced cell cycle progression and proliferation of MCF7 breast cancer cells, although SphK1 and SphK2 display different roles in mediating insulin-induced ERK1/2 and Akt activation. Moreover, the sphingosine 1-phosphate receptor 3, a key component of the SphK signaling system, is important for insulin-mediated mitogenic action in breast cancer cells. Furthermore, insulin receptor and type 1 IGF receptor (IGF1R) are responsible for the insulin-promoted mitogenic action on MCF7 breast cancer cells. Notably, IGF1R mediates insulin-stimulated phosphorylation of both SphK1 and SphK2, whereas insulin receptor is involved only in SphK1, but not SphK2, activation. Collectively the current study illustrates a new signaling system controlling the mitogenic action of insulin in breast cancer cells, suggesting a new strategy that pharmaceutically targets both isoenzymes of SphK for the management of breast cancer.