ABSTRACT
Relapse-prone, poor prognosis neuroblastoma is frequently characterized by deletion of chr1p36 where tumor suppressor gene KIF1Bß resides. Interestingly, many 1p36-positive patients failed to express KIF1Bß protein. Since altered cellular redox status has been reported to be involved in cell death and protein modification, we investigated the relationship between reactive oxygen species (ROS) and KIF1Bß. Here, we showed that wild-type KIF1Bß protein expression positively correlates with superoxide (O2-) and total ROS levels in neuroblastoma cells, unlike apoptotic loss-of-function KIF1Bß mutants. Overexpression of KIF1Bß apoptotic domain variants increases total ROS and, specifically O2-, whereas knockdown of endogenous KIF1Bß decreases ROS and O2-. Interestingly, O2- increases KIF1Bß protein expression, independent of the proteasomal degradation pathway. Scavenging O2- or ROS decreases KIF1Bß protein expression and subsequent apoptosis. Moreover, treatment with investigational redox compound Gliotoxin increases O2-, KIF1Bß protein expression, apoptosis and colony formation inhibition. Overall, our findings suggest that ROS and O2- may be important downstream effectors of KIF1Bß-mediated apoptosis. Subsequently, O2- produced may increase KIF1Bß protein expression in a positive feedback mechanism. Therefore, ROS and, specifically O2-, may be critical regulators of KIF1Bß-mediated apoptosis and its protein expression in neuroblastoma.
