Linking TNFα to sphingolipids, Sawada et al. proposed a TNFα-induced increase in Cer levels in human glioma cells via two different pathways, both of which are initiated by activation of caspase-8: first, a p53 and ROS-dependent pathway that leads to N-SMase activation via GSH depletion and thus to increased production of Cer; a second pathway activates A-SMase directly via caspase-8, and, thus, causes a ROS-independent increase in Cer levels resulting in a TNFα-induced apoptosis of human glioma cells [107]. Here, SMPD2 is linked to central nervous system cancer.