t0901317 and Breast-Neoplasms

Obesity is associated with hypercholesterolemia and is a global epidemic. Epidemiological and animal studies revealed cholesterol is an essential regulator of estrogen receptor positive (ER+) breast cancer progression while inhibition of cholesterol accumulation was found to prevent breast tumor growth. Individually, vitamin D and LXR agonist T0901317 showed anticancer properties. The present study investigated the effects of vitamin D

Topics: Apoptosis; ATP Binding Cassette Transporter 1; Breast Neoplasms; Cholesterol; Female; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; MCF-7 Cells; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Transcription Factor CHOP

Lipid rafts are cholesterol-enriched microdomains of the plasma membrane. Recent studies have underlined that their integrity is critical for cancer cell survival. Liver X receptor (LXR) has a central role in cellular cholesterol homeostasis and its stimulation inhibits proliferation of several cancer cell lines. This study investigated whether LXR could modulate lipid rafts integrity and consequently alter proliferation of the MCF-7 breast cancer cell line.. Effect of LXR agonist T0901317 on integrity of MCF-7 lipid rafts was examined by studying the expression of rafts marker flotillin-2 (FLOT2) and DHHC5, which palmitoylates FLOT2, and by studying the expression of phospho-Akt.. We demonstrated that LXR stimulation decreases mRNA and protein expression of FLOT2 and DHHC5 in MCF-7 cells. LXR stimulation also reduces Akt phosphorylation and its localization at the plasma membrane.. We showed, for the first time, that LXR regulates transcription of specific proteins of lipid rafts in a breast cancer model.

Topics: Acyltransferases; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; MCF-7 Cells; Membrane Microdomains; Membrane Proteins; Phosphorylation; Sulfonamides

Liver X receptor (LXR) plays a key role in reverse cholesterol transport by inducing the expression of the ATP-binding cassette (ABC) transporters, implicated in cholesterol efflux. Recent data showed that LXR agonists inhibit the proliferation of multiple types of human cancer cells. However, whether these effects are related to cholesterol efflux has not yet been elucidated.. Effects of two LXR agonists (TO901317 and 22(R)-hydroxycholesterol [22(R)-HC]) on proliferation, apoptosis and cholesterol efflux were examined in MCF-7 breast cancer cells.. Treatment with LXR agonists (TO901317 at 20 μM and 22(R)-HC at 2 μg/ml) inhibited proliferation and induced apoptosis of MCF-7 cells. Furthermore, LXR activation resulted in an increase in gene and protein levels of ABCG1 transporters and in cholesterol efflux to isolated high-density lipoprotein (HDL), without affecting the ABCA1/APOA-I mediated efflux. Under these conditions, a remarkable reduction of intracellular and membrane-associated cholesterol levels was observed.. LXR activation in MCF-7 cells could deprive cells of cholesterol, required for their growth, by stimulating its efflux, resulting in the inhibition of cell proliferation and in stimulation of apoptosis.

Topics: Apoptosis; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Cholesterol; Female; Humans; Hydrocarbons, Fluorinated; Hydroxycholesterols; Lipoproteins, HDL; Liver X Receptors; Orphan Nuclear Receptors; Sulfonamides