Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells

Abstract

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.

Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

“…Indeed, Apoe −/− and Abca1/g1 −/− mice were shown to have an increase in cholesterol accumulation within lipid rafts of HSCs, leading to increased signaling through the common β subunit to enhance the production of myeloid cells 37, 38. In contrast, other studies demonstrated that LXR agonist treatment disrupted the localization of key signaling molecules vascular endothelial growth factor receptor 2 and protein kinase B within lipid rafts, suggesting that activation of LXRs decreases the intracellular distribution of cholesterol to the rafts 49, 50. Thus, LXRs may be modulating lipid raft cholesterol content, which indirectly affects the identity and function of EPCs.…”

Liver X receptor β activation induces pyroptosis of human and murine colon cancer cells

“…15 Many studies have shown that LXR agonists could inhibit cancer cell proliferation by modulating cell cycle protein expression 2,8,9,16 and/or induce cancer cell death, mainly through caspase-3-dependent apoptosis. 5,7 We demonstrate here for the first time that LXR agonist activation of LXRb can induce pyroptotic cell death through an NLRP3 inflammasome-dependent caspase-1 activation pathway. This effect seems to be quite surprising, as many studies report that LXR is mainly a negative regulator of inflammation by downregulating the expression of selective inflammatory genes (e.g., il1b, il6, inos, cox2, mmp9, mcp1, mcp3) through a process that involves DNA interaction, known as transrepression.…”

Cross-talk between the Androgen Receptor and the Liver X Receptor

“…Indeed, it has been shown that LXR reduces growth of PCa cells and xenografts (56,57), delaying the progression to androgen independence in a xenograft model (58). This has been attributed to cholesterol depletion, which disrupts cholesterol-rich lipid rafts and thus down-regulates Akt activity (57).…”