«7ß-hydroxycholesterol-induced energy stress leads to sequential opposing signaling responses and to death of C6 glioblastoma cells»

Biochemical Pharmacology

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This article has been published in Biochemical Pharmacology

Authors :
Ludovic Clarion, Mathilde Schindler, Jan de Weille, Karine Lolmède, Audrey Laroche-Clary, Emmanuelle Uro-Coste, Jacques Robert, Marcel Mersel, Norbert Bakalara

Abstract :
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.