D,L-Sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells.
D,L-Sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells.
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DOI：
10.1158/1535-7163.mct-09-0104
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发表时间：
2009-07
影响因子：
5.7
通讯作者：
Singh SV
中科院分区：
文献类型：
--
作者：
Kim SH;Singh SV
D，L-萝卜硫素（SFN），一种十字花科植物衍生的L-异构体的合成类似物，在培养和体内抑制人前列腺癌细胞的生长，并在前列腺癌转基因小鼠模型中延缓癌症发展。我们现在证明，SFN治疗导致雄激素受体（AR）在LNCaP和C4-2人前列腺癌细胞在药理学浓度的转录抑制。LNCaP和C4-2细胞暴露于SFN导致总AR蛋白水平以及Ser 210/213磷酸化AR的浓度和时间依赖性降低。SFN介导的AR蛋白水平下降伴随着细胞内以及前列腺特异性抗原（AR调节的基因产物）分泌水平的降低。在蛋白质合成抑制剂放线菌酮的存在下，SFN暴露导致的AR蛋白水平的下降并没有逆转。RT-PCR分析显示AR mRNA水平呈剂量依赖性降低，表明该配体激活的转录因子的转录抑制。SFN处理抑制AR启动子活性，如荧光素酶报告基因测定所示。合成雄激素（R1881）刺激的AR核转位显着抑制SFN的存在下，在两个细胞系。SFN处理还抑制R1881刺激的LNCaP细胞增殖。天然存在的硫代-（iberverin，芥酸，和berteroin），但不是磺酰基类似物（cheirolin，erysolin，和alyssin砜），SFN也有效地降低蛋白水平的AR在LNCaP细胞。总之，本研究首次表明，SFN治疗导致AR的转录抑制和抑制其在人前列腺癌细胞中的核定位。
D,L-sulforaphane (SFN), a synthetic analogue of cruciferous-vegetable derived L-isomer, inhibits growth of human prostate cancer cells in culture and in vivo and retards cancer development in a transgenic mouse model of prostate cancer. We now demonstrate that SFN treatment causes transcriptional repression of androgen receptor (AR) in LNCaP and C4-2 human prostate cancer cells at pharmacological concentrations. Exposure of LNCaP and C4-2 cells to SFN resulted in a concentration- and time-dependent decrease in protein levels of total AR as well as Ser210/213 phosphorylated AR. The SFN-mediated decline in AR protein level was accompanied by a decrease in intracellular as well as secreted levels of prostate specific antigen, an AR-regulated gene product. Decrease in AR protein level resulting from SFN exposure was not reversed in the presence of protein synthesis inhibitor cycloheximide. RT-PCR analysis revealed dose-dependent decrease in AR mRNA levels indicating transcriptional repression of this ligand-activated transcription factor. The SFN treatment inhibited AR promoter activity as revealed by luciferase reporter assay. Synthetic androgen (R1881)-stimulated nuclear translocation of AR was markedly suppressed in the presence of SFN in both cell lines. The SFN treatment also inhibited R1881-stimulated proliferation of LNCaP cells. Naturally occurring thio- (iberverin, erucin, and berteroin), but not the sulfonyl-analogues (cheirolin, erysolin, and alyssin sulfone), of SFN were also effective in reducing protein levels of AR in LNCaP cells. In conclusion, the present study demonstrates for the first time that SFN treatment causes transcriptional repression of AR and inhibition of its nuclear localization in human prostate cancer cells.