Lycopene inhibits the proliferation of androgen-dependent human prostate tumor cells through activation of PPAR gamma-LXR alpha-ABCA1 pathway

Abstract

The activation of nuclear receptors, peroxisome proliferator-activated receptor gamma (PPAR gamma) and liver X receptor alpha (LXR alpha), has been shown to inhibit the growth of prostate cancer cells. This study examined whether the anti-proliferative effect of lycopene on androgen-dependent human prostate cancer (LNCaP) cells involves the up-regulation of the expression of PPAR gamma and LXR alpha. As expected, lycopene treatment (2.5-10 mu M) significantly inhibited the proliferation of LNCaP cells during incubation for 96 h. Lycopene significantly increased the protein and mRNA expression of PPAR gamma and LXR alpha at 24 and 48 h, while the increased in the expression of ATP-binding cassette transporter 1 (ABCA1) was only evident 96 h. In addition, lycopene significantly decreased cellular total cholesterol levels and increased apoA1 protein expression at 96 h. Incubation of LNCaP cells with lycopene (10 mu M) in the presence (20 mu M) of a specific antagonist of PPAR gamma (GW9662) and LXR alpha (GGPP) restored the proliferation of LNCaP cells to the control levels and significantly suppressed protein expression of PPAR gamma and LXR alpha as well as increased cellular total cholesterol levels. LXR alpha knockdown by siRNA against LXR alpha significantly enhanced the proliferation of LNCaP cells, whereas si-LXR alpha knockdown followed by incubation with lycopene (10 mu M) restored the proliferation to the control level. The present study is the first to demonstrate that the anti-proliferative effect of lycopene on LNCaP cells involves the activation of the PPAR gamma-LXR alpha-ABCA1 pathway, leading to reduced cellular total cholesterol levels. (C) 2012 Elsevier Inc. All rights reserved.