Bmc Cancer, 2011, 11(1):1-9.

Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity

Wentao Qi, et al

Department of Medicine, Division of Gastroenterology, NorthShore University Research Institute, Evanston, IL 60201, USA.

BACKGROUND: Soy consumption is associated with a lower incidence of colon cancer which is believed to be mediated by one of its of components, genistein. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation, but mechanisms are not well understood. Epidermal growth factor (EGF)-induced proliferation of colon cancer cells plays an important role in colon cancer progression and is mediated by loss of tumor suppressor FOXO3 activity. The aim of this study was to assess if genistein exerts anti-proliferative properties by attenuating the negative effect of EGF on FOXO3 activity.

METHODS: The effect of genistein on proliferation stimulated by EGF-mediated loss of FOXO3 was examined in human colonic cancer HT-29 cells. EGF-induced FOXO3 phosphorylation and translocation were assessed in the presence of genistein. EGF-mediated loss of FOXO3 interactions with p53 (co-immunoprecipitation) and promoter of p27kip1 (ChIP assay) were examined in presence of genistein in cells with mutated p53 (HT-29) and wild type p53 (HCT116). Silencing of p53 determined activity of FOXO3 when it is bound to p53.

RESULTS: Genistein inhibited EGF-induced proliferation, while favoring dephosphorylation and nuclear retention of FOXO3 (active state) in colon cancer cells. Upstream of FOXO3, genistein acts via the PI3K/Akt pathway to inhibit EGF-stimulated FOXO3 phosphorylation (i.e. favors active state). Downstream, EGF-induced disassociation of FOXO3 from mutated tumor suppressor p53, but not wild type p53, is inhibited by genistein favoring FOXO3-p53(mut) interactions with the promoter of the cell cycle inhibitor p27kip1 in colon cancer cells. Thus, the FOXO3-p53(mut) complex leads to elevated p27kip1 expression and promotes cell cycle arrest.

CONCLUSION: These novel anti-proliferative mechanisms of genistein suggest a possible role of combining genistein with other chemoreceptive agents for the treatment of colon cancer.

英国《BMC癌症》，2011年6月

染料木黄酮通过减弱表皮生长因子对肿瘤抑制因子 FOXO3 活性的负面作用抑制结肠癌细胞增殖

齐文涛等

美国北岸大学研究院胃肠病学院医学系

背景︰ 大豆消耗由于其所含的成分染料木黄酮被认为与结肠癌发病率较低有关。染料木黄酮可能通过诱导细胞凋亡和抑制细胞增殖来抑制癌症发展，但是其作用机制目前还不太清楚。表皮生长因子 (EGF)-诱导的结肠癌细胞增殖在结肠肿瘤发展中发挥着重要作用，并且由肿瘤抑制因子FOXO3 活性的损失调整。本研究的目的是评估染料木黄酮是否通过减弱 EGF 对 FOXO3 活性的负面作用进而产生抗增殖特性。

方法︰ 在人体大肠癌细胞HT29考察了染料木黄酮对EGF-介导FOXO3的损失诱导的细胞增殖的影响。在染料木黄酮存在时，评估EGF-诱导 FOXO3的 磷酸化和易位。当金雀异黄素在 p53 突变细胞(HT-29) 和野生型 p53 细胞(HCT116)中存在时，检测EGF-介导FOXO3的损失与p53 蛋白 （免疫共沉淀）的相互作用和p27kip1启动子（芯片检测）。当它绑定到 p53中时，p53 的静止确定了FOXO3的活性。

结果︰当在结肠癌细胞中倾向于去磷酸化和细胞核保留 FOXO3 （激活状态）时，金雀异黄素抑制了EGF-诱导的细胞增殖。在FOXO3的上游，金雀异黄素通过 PI3K/Akt 途径抑制EGF-激发 FOXO3 磷酸化 （例如促进激活状态）。在结肠癌细胞中，下游，EGF-诱导FOXO3 从非野生型p53 突变肿瘤细胞中分离，被金雀异黄素倾向于FOXO3-p53(变换) 与细胞周期抑制剂 p27kip1启动子的相互作用来抑制。因此，FOXO3-p53(mut) 复合物导致p27kip1的表达上升，促进细胞周期阻滞。

结论︰ 这些金雀异黄素新型抗增殖作用的机制表明了在治疗结肠癌时其他化学治疗药物联合金雀异黄素可能发挥的作用。