Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells
Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells
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DOI：
10.1093/jn/136.1.75
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发表时间：
2006-01-01
影响因子：
4.2
通讯作者：
Shiverick, KT
中科院分区：
文献类型：
--
作者：
Handayani, R;Rice, L;Shiverick, KT
亚洲饮食中大豆异黄酮的高消费量与临床上重要的前列腺癌病例的发病率较低有关。这些饮食的化学预防特性可能是由几种类型的异黄酮类化合物（包括染料木素和大豆苷元）的相互作用引起的。本研究探讨了大豆浓缩物（ISF）对PC-3人前列腺癌细胞生长和基因表达谱的影响。台盼蓝拒染法和[H-3]-胸苷掺入法显示，ISF分别降低细胞活力和导致DNA合成的剂量依赖性抑制，在52 mg/L时DNA合成的50%抑制（IC 50）（P = 0.05）。ISF中染料木素和大豆苷元的糖苷结合物在细胞培养中转化为具有生物活性的游离苷元，并与DNA合成的抑制有关。流式细胞术和Western免疫印迹分析显示，200 mg/L的ISF可使G2/M期细胞增多（P < 0.05），细胞周期蛋白A（cyclin A）减少20%（P < 0.05）。使用询问类似于17，000个人类基因的Affytron寡核苷酸DNA微阵列分析ISF对PC-3细胞基因表达谱的影响。在75个基因中，28个基因表达上调，47个基因表达下调（P < 0.05）。进一步的分析表明，IL-8，基质金属蛋白酶13，卵泡抑素6 A，和纤连蛋白的mRNA水平显着降低，而表达的p21（CIP 1），一个主要的细胞周期抑制蛋白，增加。在高和低ISF浓度下验证ISF对IL-8和p21（CIP 1）mRNA和蛋白表达的影响。我们的数据表明，ISF通过调节细胞周期进程和参与细胞周期调控、转移和血管生成的基因的表达来抑制PC-3细胞的生长。
High consumption of soy isoflavones in Asian diets has been correlated with a lower incidence of clinically important cases of prostate cancer. The chemopreventive properties of these diets may result from an interaction of several types of isoflavones, including genistein and daidzein. The present study investigated the effects of a soy isoflavone concentrate (ISF) on growth and gene expression profiles of PC-3 human prostate cancer cells. Trypan blue exclusion and [H-3]-thymidine incorporation assays showed that ISF decreased cell viability and caused a dose-dependent inhibition of DNA synthesis, respectively, with 50% inhibition (IC50) of DNA synthesis at 52 mg/L (P = 0.05). The glucoside conjugates of genistein and daidzein in ISF were converted to bioactive free aglycones in cell culture in association with the inhibition of DNA synthesis. Flow cytometry and Western immunoblot analyses showed that ISF at 200 mg/L caused an accumulation of cells in the G(2)/M phase of the cell cycle (P < 0.05) and decreased cyclin A by 20% (P < 0.05), respectively. The effect of ISF on the gene expression profile of PC-3 cells was analyzed using Affymetrix oligonucleotide DNA microarrays that interrogate similar to 17,000 human genes. Of the 75 genes altered by ISF, 28 were upregulated and 47 were downregulated (P < 0.05). Further analysis showed that IL-8, matrix metalloproteinase 13, inhibin 6 A, follistatin, and fibronectin mRNA levels were significantly reduced, whereas the expression of p21(CIP1), a major cell cycle inhibitory protein, was increased. The effects of ISF on the expression of IL-8 and p21(CIP1) mRNA and protein were validated at high and low ISF concentrations. Our data show that ISF inhibits the growth of PC-3 cells through modulation of cell cycle progression and the expression of genes involved in cell cycle regulation, metastasis, and angiogenesis.