Ligand, receptor, and cell type–dependent regulation of ABCA1 and ABCG1 mRNA in prostate cancer epithelial cells
Ligand, receptor, and cell type–dependent regulation of ABCA1 and ABCG1 mRNA in prostate cancer epithelial cells
复制标题
DOI：
10.1158/1535-7163.mct-09-0020
复制
发表时间：
2009-07
影响因子：
5.7
通讯作者：
S. Trasino;Y. S. Kim;Thomas T. Y. Wang
中科院分区：
文献类型：
--
作者：
S. Trasino;Y. S. Kim;Thomas T. Y. Wang
最近的证据表明肝脏 X 受体 (LXR) 是前列腺癌的潜在抗癌靶点。然而，两种 LXR 亚型 LXRα 或 LXRβ 中哪一种调节转化前列腺上皮细胞中的 LXR 响应基因 ATP 结合盒亚家族成员 A1 (ABCA1) 和 G1 (ABCG1) 的特征很少。在本研究中，使用小干扰RNA (siRNA)来确定LXRα或LXRβ是否参与调节LNCaP和PC-3细胞中ABCA1和ABCG1 mRNA表达。用合成的 LXR 配体 T0901317 和氧化甾醇：25-羟基胆固醇 (25HC) 和 24(S), 25-环氧胆固醇 (24,25EC) 处理这两种细胞系，导致 ABCA1 和 ABCG1 mRNA 表达增加超过 10 倍。用针对 LXRβ 或 LXRα 的 siRNA 转染 LNCaP 细胞未能抑制 T0901317 和 25HC 介导的 ABCA1 mRNA 增加。然而，LXRβ 的 siRNA 沉默确实抑制了 24,25EC 处理的 LNCaP 细胞中的 ABCA1 mRNA 表达。相反，LXRβ siRNA抑制T0901317、25HC和24,25EC对PC-3细胞中ABCA1 mRNA的诱导以及LNCaP和PC-3细胞中ABCG1 mRNA的诱导。其他实验表明，T0901317 和 25HC 对 ABCA1 mRNA 表达的诱导被 p38 应激激酶拮抗剂 SB202190 和 PKA 抑制剂 H89 显着抑制。我们的研究首次表明，LXRβ（而非 LXRα）是 LNCaP 和 PC-3 细胞中 ABCG1 mRNA 表达的主要调节亚型。我们的研究还表明，ABCA1 基因表达受到合成和天然 LXR 配体的差异调节，可能涉及激酶介导的信号转导。 [摩尔癌症疗法 2009;8(7):1934–45]
Recent evidence suggests that the liver X receptor (LXR) is a potential anticancer target in prostate carcinoma. There is little characterization, however, of which of the two LXR isoforms, LXRα or LXRβ, regulates the LXR-responsive genes ATP-binding cassette subfamily members A1 (ABCA1) and G1 (ABCG1) in transformed prostatic epithelial cells. In this study, small interfering RNA (siRNA) was used to determine whether LXRα or LXRβ is involved in regulating ABCA1 and ABCG1 mRNA expression in LNCaP and PC-3 cells. Treatment of both cell lines with the synthetic LXR ligand T0901317 and oxysterols: 25-hydroxycholesterol (25HC) and 24(S), 25-epoxycholesterol (24,25EC), resulted in more than a 10-fold increase of ABCA1 and ABCG1 mRNA expression. Transfection of LNCaP cells with siRNA against either LXRβ or LXRα failed to inhibit T0901317 and 25HC-mediated increase of ABCA1 mRNA. siRNA silencing of LXRβ did, however, inhibit ABCA1 mRNA expression in 24,25EC-treated LNCaP cells. In contrast, LXRβ siRNA inhibited T0901317, 25HC, and 24,25EC induction of ABCA1 mRNA in PC-3 cells and ABCG1 mRNA in both LNCaP and PC-3 cells. Additional experiments revealed that T0901317 and 25HC induction of ABCA1 mRNA expression was significantly inhibited by the p38 stress kinase antagonist SB202190 and PKA inhibitor H89. Our study is the first to show that LXRβ, but not LXRα, is the major regulatory isoform of ABCG1 mRNA expression in LNCaP and PC-3 cells. Our study also reveals that ABCA1 gene expression is differentially regulated by synthetic and natural LXR ligands, possibly involving kinase mediated signal transduction. [Mol Cancer Ther 2009;8(7):1934–45]