Figure 9. Vacuolating sphingolipid SH-BC-893 targets primary and adaptive pathways for nutrient acquisition.

Like ceramide, the synthetic sphingolipid SH-BC-893 activates PP2A to downregulate nutrient transporters. In addition, SH-BC-893 activates a second PP2A complex, PP2A′ that is not affected by ceramide. Activation of PP2A′ leads to mislocalization of PIKfyve and PI(3,5)P₂, reducing lysosomal fusion reactions. Because PI(3,5)P₂ is membrane anchored and cannot diffuse to its target, loss of PI(3,5)P₂ (YM201636 treatment) and PI(3,5)P₂ mislocalization (SH-BC-893 treatment) produce similar phenotypes. While ceramide limits access to extracellular nutrients, SH-BC-893 blocks access to both extracellular and intracellular nutrients. Substrate limitation in the context of oncogene-driven anabolism is lethal, while nontransformed cells can make adaptive metabolic changes that allow them to survive nutrient stress.