Cholesterol is a structural component of
lipid rafts within the plasma membrane. These domains, used as platforms for various signaling molecules, regulate cellular processes including cell survival.
Cholesterol contents are tightly correlated with the structure and function of
lipid rafts.
Liver X receptors (LXRs) have a central role in the regulation of
cholesterol homeostasis within the cell. Therefore, we investigated whether these
nuclear receptors could modulate
lipid raft signaling and consequently alter
prostate cancer (PCa) cell survival. Treatment with the synthetic LXR agonist
T0901317 downregulated the AKT survival pathway and thus induced apoptosis of LNCaP PCa cells in both xenografted nude mice and cell culture. The decrease in
tumor cholesterol content resulted from the upregulation of ABCG1 and the subsequent increase in reverse
cholesterol transport. RNA interference experiments showed that these effects were mediated by LXRs. Atomic force microscopy scanning of the inner plasma membrane sheet showed smaller and thinner
lipid rafts after LXR stimulation, associated with the downregulation of AKT phosphorylation in these
lipid rafts. Replenishment of cell membranes with exogenous
cholesterol antagonized these effects, showing that
cholesterol is a key modulator in this process. Altogether, pharmacological modulation of LXR activity could thus reduce prostate
tumor growth by enhancing apoptosis in a
lipid raft-dependent manner.