«7ß-hydroxycholesterol-induced energy stress leads to sequential opposing signaling responses and to death of C6 glioblastoma cells»
Related experiences were cofinanced or supported by INCa, Inserm and Beta Innov.
This article has been published in Biochemical Pharmacology
Ludovic Clarion, Mathilde Schindler, Jan de Weille, Karine Lolmède, Audrey Laroche-Clary, Emmanuelle Uro-Coste, Jacques Robert, Marcel Mersel, Norbert Bakalara
We have previously demonstrated that 7b-Hydroxycholesterol cytotoxicity in vivo and in vitro depends on the accumulation of its esters. We show in this study that lipid rafts isolated from 7b-hydroxycholesterol-treated C6 cells accumulate cholesterol and oxysterol esters. These modifications in lipid content are accompanied by a redistribution of flotillin-1 in the lipid rafts. Transient increases of AMPK phosphorylation and mitochondrial activity during the first 6-12 h of 7b-hydroxycholesterol treatment indicate that C6 cells undergo energy stress and increase oxidative phosphorylation. Even so, ATP levels are maintained during 15 h until glucose uptake decreases. The persistence of 7b-hydroxycholesterol-induced stress led after 12h to Akt activation followed after 24 h by P38 activation, loss of GSK3b activation and cell death. Finally we demonstrate that the observed signaling responses depend on 7b-hydroxycholesterol esterification, confirming that esterification of 7b-hydroxycholesterol is essential for cytotoxicity.