Fig. 6.

Rationale for simultaneous targeting of SK and Raf for cancer chemotherapy. Features in green represent pro-proliferative components, while features in red represent pro-apoptotic components. A variety of growth-stimulatory and angiogenic factors promote signaling through the Ras-Raf-MEK-ERK pathway that drives proliferation. Concurrently, these stimuli activate the sphingolipid metabolism pathway resulting in sequential the conversion of sphingomyelin to ceramide, sphingosine and S1P, which also drive proliferation. Crosstalk between the two pathways occurs at the level of SK, since S1P enhances the activation of Ras, and ERK phosphorylates and thereby stimulates SK activity. Treatment with sorafenib acts on components in the Ras-Raf-MEK-ERK pathway, while the SK inhibitors attenuate S1P-mediated proliferation. Importantly, dual inhibition of the interacting pathways prevents the amplification of signaling cycle, providing synergistic reduction in tumor cell proliferation