Liver X receptor agonist inhibits proliferation of ovarian carcinoma cells stimulated by oxidized low density lipoprotein

Abstract
Objectives
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 μg/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 μM and > 60 μM 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.

Daniel R. Scolesa, b, , , Xuan Xua, Haimei Wangc, Hang Trana, Barbie Taylor-Hardingb, Andrew Lia, b and Beth Y. Karlana, b

aWomen'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

bDepartment of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

cDivision of Cardiothoracic Surgery, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, USA

Received 17 April 2009. Available online 24 October 2009.