Cancer preventive phytochemicals uniquely activate liver x receptor responsive genes through receptor dependent and independent mechanisms in prostate cancer cells

Abstract

Activation of liver X receptor (LXR) in models of prostate cancer (PCa) results in reduction of cell growth and hormone signaling. We hypothesized that cancer protective phytochemicals may interact with the LXR pathway in an in vitro model of PCa. In the present study we examined the effects of three diet‐derived cancer preventive phytochemicals: genistein, resveratrol, and diindolylmethane (DIM), on activation of two classic LXR responsive genes ATP binding cassette transporter A1 and G1, (ABCA1) and (ABCG1) mRNA in LNCaP human prostate cancer cells. LNCaP cells treated with either 5 μM genistein, resveratrol or DIM resulted in a 3‐7 fold increase in ABCG1 and ABCA1 mRNA levels. Using siRNA technology, we also examined which LXR isotype (LXRα or LXRβ) may be involved in any interactions between these phytochemicals and the LXR pathway. Transfection of LNCaP cells with LXRβ siRNA, but not LXRα siRNA, completely inhibited genistein's ability to induce ABCG1 mRNA but only had a partial effect on DIM. Use of siRNA against LXRα or LXRβ had no effect on resveratrol's induction of ABCG1 mRNA. Increased ABCA1 mRNA expression by all three phytochemicals could not be reversed by either LXRα or LXRβ siRNA. Our data revealed that in LNCaP cells: i) Dietary phytochemicals activate mRNA expression of LXR responsive genes ABCA1 and ABCG1, and ii) Genistein and DIM can modulation ABCG1 mRNA with a unique requirement for the LXRβ isoform.