K-ATP channel block prevents proteasome inhibitor-induced apoptosis in differentiated PC12 cells

Abstract

Dysfunction of the proteasome system has been suggested to be implicated in neuronal degeneration. Modulation of K-ATP channels appears to affect the viability of neuronal cells exposed to toxic insults. However, the effect of K-ATP channel blockers on the neuronal cell death mediated by proteasome inhibition has not been studied. The present study investigated the effect of K-ATP channel blockers on proteasome inhibitor-induced apoptosis in differentiated PC12 cells and SH-SY5Y cells. 5-Hydroxydecanoate (a selective K-ATP channel blocker) and glibenclamide (a cell surface and mitochondrial K-ATP channel inhibitor) reduced the proteasome inhibitor-induced apoptosis. Addition of the K-ATP channel blockers attenuated the proteasome inhibitor-induced changes in the levels of apoptosis-related proteins, the loss of the mitochondrial transmembrane potential, the increase in the formation of reactive oxygen species and the depletion of glutathione in both cell lines. The results show that K-ATP channel blockers may attenuate proteasome inhibitor-induced apoptosis in PC12 cells by suppressing activation of the mitochondrial pathway and of the caspase-8- and Bid-dependent pathways. The preventive effect appears to be associated with the inhibition of the formation of reactive oxygen species and the depletion of glutathione. K-ATP channel blockade appears to prevent proteasome inhibition-induced neuronal cell death. (C) 2015 Elsevier B.V. All rights reserved.