Cholesterol level of lipid raft microdomains regulates apoptotic cell death in prostate cancer cells through EGFR-mediated Akt and ERK signal transduction

Abstract

BACKGROUND: Lipid rafts are cholesterol-enriched microdomains in cell membranes that have been shown to regulate signal transduction. We investigated whether membrane cholesterol could regulate apoptosis and attempted to elucidate the mechanism by which apoptosis is induced in prostate cancer cells. METHODS: LNCaP cells were exposed to 2-hydroxyprophyl-beta-cyclodextrin (HPCD) to deplete membrane cholesterol. Cell viability and apoptosis were evaluated by Celltiter Bluetrade mark Cell Viability assay and ethidium bromide/acridine orange staining. Signal transduction was investigated by immunoblot analysis of cell lysates. RESULTS: Cell viability was dose dependent inhibited by HPCD and restored by replenishment of cholesterol. HPCD induced apoptotic cell death through down-regulation of Bcl-xL and up-regulation of caspase-3 and PARP cleavages. HPCD inhibited both EGFR/Akt and EGFR/ERK signal transduction. CONCLUSIONS: Lipid raft cholesterol regulates apoptotic cell death in prostate cancer cells through EGFR-mediated Akt and ERK pathways.