Oxidized low density lipoprotein (LDL) stimulates ovarian carcinoma proliferation that is inhibited by the LXR agonist T0901317

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Obesity negatively impacts the survival of ovarian cancer patients. We recently reported outcomes data from 216 ovarian cancer patients and demonstrated that obesity was associated with reduced progression free and overall survival, and that obesity was an independent predictor of survival. To investigate the underlying mechanism that accounts for this association, we examined the effect of oxidized low density lipoprotein (LDL) and the liver X receptor (LXR) agonist T0901317 on ovarian cancer cell growth. Increases in oxidized LDL are associated with obesity and other obesity-related disorders including atherosclerosis and diabetes. The LXR nuclear receptors (LXRα and LXRβ) are dietary cholesterol sensors that when activated stimulate lipid efflux from cells by activating ATP binding cassette transporter genes (ABCA1 and others). T0901317 is a synthetic nonsteroidal ligand to LXR that mediates lipid efflux by ABCA1, and in mouse models, increases plasma HDL, stimulates cholesterol excretion, and reduces liver cholesterol. We treated 3 ovarian cancer cell lines (CAOV3, OVCAR3 and SKOV3) with oxidized LDL and measured the resultant changes in proliferation by MTT assays. A dose-dependent increase in cellular proliferation was seen with increasing oxidized LDL concentration. We determined that concentrations of T0901317 between 100-250 ng/ml significantly inhibited the proliferation of all 3 cell lines while higher doses had no effects. Combinations of oxidized LDL and T0901317 were investigated: CAOV3, OVCAR3 and SKOV3 growth was stimulated with 50 μg/ml oxidized LDL but this effect was almost completely reversed with the addition of 100 ng/ml T0901317. Among the three lines, OVCAR3 was most responsive to oxidized LDL with 40% growth stimulation but only 10% in the presence of T0901317. T0901317 reversal of oxidized LDL-mediated proliferation confirmed that intracellular LDL was responsible for growth stimulation. We are now investigating how oxidized LDL might reduce the sensitivity of these ovarian carcinoma cell lines to cisplatin. There are few studies on the effects of cholesterol on cancer proliferation and the beneficial effects of statins on cancer growth. These data demonstrate that proliferation of ovarian cancer cells can be stimulated by cholesterol. Dietary or genetically mediated increases in circulating cholesterol in obese ovarian cancer patients may contribute to the aggressive ovarian cancer biology observed in clinical studies.