Oxidative stress‐induced activation of Lyn recruits sphingomyelinase and is requisite for its stimulation by Ara‐C

This is the authors' abstract. We don't add key points for this paper.

Induction of apoptosis is considered to be the underlying mechanism that accounts for the efficiency of chemotherapeutic drugs. The identification of ceramide as a key mediator of apoptosis has made it possible to identify cellular entities that regulate drug‐induced sphingomyelinase activation. Using human leukemia cell lines, we demonstrate that 1‐β‐D‐arabinofuranosylcytosine (Ara‐C) stimulated ceramide generation, which was dependent on reactive oxygen species (ROS). Co‐immunoprecipitation studies revealed that Ara‐C‐generated ROS activated the scr kinase p53/p56 Lyn, which then recruited neutral sphingomyelinase and was responsible for its activation. These effects were blocked by herbimycin A and Lyn antisense oligonucleotides. In conclusion, this study establishes a series of events in which early ROS generated by Ara‐C leads to Lyn‐dependent neutral sphingomyelinase activation, JNK phosphorylation, and apoptosis.