Liver X receptor agonist inhibits proliferation of ovarian carcinoma cells stimulated by oxidized low density lipoprotein.
OBJECTIVE
We previously observed an association between ovarian cancer outcome and statin use and hypothesized lipoproteins have direct effects on ovarian cancer proliferation. Here we investigate the direct effects of low density lipoprotein (LDL) and oxidized LDL (oxLDL) on proliferation and the inhibitory effects of fluvastatin and a liver X receptor (LXR) agonist.


METHODS
The effects of LDL, oxLDL, the LXR agonist TO901317, fluvastatin and cisplatin on cellular proliferation were determined using MTT assays. LXR pathway proteins were assayed by immunoblotting. Cytokine expression was determined by antibody array.


RESULTS
Concentrations of oxLDL as small as 0.1 microg/ml stimulated CAOV3 and SKOV3 proliferation, while LDL had no effect. TO901317 inhibited the proliferation of CAOV3, OVCAR3 and SKOV3 cells stimulated by oxLDL. Fluvastatin inhibited oxLDL mediated proliferation of CAOV3 and SKOV3. Cardiotrophin 1 (CT-1) was mitogenic to CAOV3 and SKOV3, was induced by oxLDL, and was reversed by TO901317. OxLDL increased cisplatin IC50s by 3.8 microM and > 60 microM for CAOV3 and SKOV3 cells, respectively. The LXR pathway proteins CD36, LXR, and ABCA1 were expressed in eight ovarian carcinoma cell lines (A2780, CAOV3, CP70, CSOC882, ES2, OVCAR3, SKOV3).


CONCLUSIONS
OxLDL reduced ovarian carcinoma cell chemosensitivity and stimulated proliferation. These effects were reversed by LXR agonist or fluvastatin. The LXR agonist also inhibited expression of the ovarian cancer mitogen CT-1. These observations suggest a biologic mechanism for our clinical finding that ovarian cancer survival is associated with statin use. Targeting LXR and statin use may have a therapeutic role in ovarian cancer.
Women's Cancer Research Institute and Division of Gynecologic Oncology, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, USA. Daniel.Scoles@hsc.utah.edu
Daniel R
DR
Scoles
Xuan
X
Xu
Haimei
H
Wang
Hang
H
Tran
Barbie
B
Taylor-Harding
Andrew
A
Li
Beth Y
BY
Karlan
D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D005229:Fatty Acids, Monounsaturated; D000077340:Fluvastatin; D006845:Hydrocarbons, Fluorinated; D007211:Indoles; D008024:Ligands; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C099252:oxidized low density lipoprotein