Insulin-like growth factor-I regulates glucose-induced mithochondrial depolarization and apoptosis in human neuroblastoma

Abstract

Neuroblastoma, a pediatric peripheral nervous system tumor, frequently contains alterations in apoptotic pathways, producing chemoresistant disease. Insulin-like growth factor (IGF) system components are highly expressed in neuroblastoma, further protecting these cells from apoptosis. This study investigates IGF-I regulation of apoptosis at the mitochondrial level. Elevated extracellular glucose causes rapid mitochondrial enlargement coupled with an increase in the mitochondrial membrane potential (ΔΨM) followed by mitochondrial membrane depolarization (MMD), uncoupling protein 3 (UCP3) downregulation, caspase-3 activation and decreased Bcl-2. MMD inhibition by Bongkrekic acid prevents high-glucose-induced loss of UCP3 and apoptosis. Glucose exposure induces caspase-9 cleavage within 30 min, and caspase-9 inhibition prevents glucose-mediated apoptosis. IGF-I prevents caspase activation and mitochondrial events leading to apoptosis. These results suggest that elevated glucose produces early initiator caspase activation, followed by ΔΨM changes, in neuroblastoma cells; in turn, IGF-I prevents apoptosis by preventing downstream caspase activation, maintaining ΔΨM and regulating Bcl proteins. © 2004 Nature Publishing Group All rights reserved.