Dietary genistein inhibits metastasis of human prostate cancer in mice
Dietary genistein inhibits metastasis of human prostate cancer in mice
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DOI：
10.1158/0008-5472.can-07-1246
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Bergan, Raymond C.
中科院分区：
文献类型：
--
作者：
Lakshman, Minalini;Xu, Li;Bergan, Raymond C.
膳食染料木素与降低前列腺癌（PCa）死亡率有关。转移是前列腺癌死亡的最终原因。细胞脱离和侵袭是转移级联的早期步骤。我们已经证明染料木素在体外抑制PCa细胞脱离和细胞侵袭。我们已经证明染料木素介导的局灶黏着激酶（FAK）和p38丝裂原活化蛋白激酶(MAPK)-热休克蛋白27 （HSP27）通路的激活抑制分别调节PCa细胞脱离和侵袭作用。为了评估染料木素的抗转移潜力，我们建立了一个适合于评估抗转移药物疗效的动物模型。原位植入人PC3-M型PCa细胞4周后在b> %的近交系胸腺小鼠中形成肺微转移。在植入前给老鼠喂食染料木素，其血液浓度与服用染料木素的人相似。染料木素减少转移96%，诱导PC3-M细胞的核形态变化，表明黏附增加（即脱落减少），但没有改变肿瘤生长。染料木素增加FAK、p38 NLAPK和HSP27“促进性”蛋白的肿瘤水平。然而，磷酸化蛋白与总蛋白的比例呈下降趋势，表明激活蛋白的相对数量没有增加。本研究描述了一种适合于测试抗转移药物的人类前列腺癌转移的小鼠模型。这是第一次表明膳食中染料木素浓度可以抑制前列腺癌细胞的转移。促进性蛋白的增加支持了细胞对治疗诱导的抗运动效应的代偿反应的概念。人类抗转移疗效的研究是有必要的，并且正在进行中。
Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in >80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 NLAPK, and HSP27 "promotility" proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way.