Sulforaphane inhibits angiogenesis through activation of FOXO transcription factors
Sulforaphane inhibits angiogenesis through activation of FOXO transcription factors
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DOI：
10.3892/or_00000589
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发表时间：
2009-12-01
期刊：
影响因子：
4.2
通讯作者：
Shankar, Sharmila
中科院分区：
文献类型：
--
作者：
Davis, Rachel;Singh, Karan P.;Shankar, Sharmila
最近的研究表明，萝卜硫素，一种主要存在于十字花科蔬菜中的化合物，可以通过调节血管生成来抑制肿瘤生长。然而，其抑制血管生成的分子机制尚未见报道。在本研究中，我们研究了萝卜硫素(SNF)通过调节FOXO转录因子抑制人脐静脉内皮细胞(HUVECs)血管生成的分子机制。抑制MEK/ERK和PI3K/AKT通路协同抑制HUVEC的细胞迁移和毛细血管形成，并进一步增强萝卜硫素的抗血管生成作用。MEK和AKT激酶的抑制剂协同增强FOXO3a的核转位。抑制MEK/ERK和PI3K/AKT通路协同诱导FOXO转录活性，抑制细胞迁移和毛细管形成；在萝卜硫素存在下，这些事件进一步增强。FOXO的磷酸化缺陷突变体通过激活FOXO转录因子来增强萝卜硫素的抗血管生成作用。综上所述，萝卜硫素激活FOXO转录因子可能是抑制血管生成的重要生理过程，最终可能控制肿瘤的生长。萝卜硫素的这些新的抗血管生成活性可能有助于其癌症的化学预防和治疗潜力。
Recent studies have suggested that sulforaphane, a compound found largely in cruciferous vegetables, could inhibit tumor growth through regulation of angiogenesis. However, the molecular mechanism by which it inhibits angiogenesis has not been reported. In this study, we examined the molecular mechanisms by which sulforaphane (SNF) inhibits angiogenesis through regulation of FOXO transcription factor in human umbilical vein endothelial cells (HUVECs). Inhibition of MEK/ERK and PI3K/AKT pathways synergistically inhibited cell migration and capillary tube formation by HUVECs and further enhanced the anti-angiogenic effects of sulforaphane. Inhibitors of MEK and AKT kinases synergistically enhanced nuclear translocation of FOXO3a. Inhibition of the MEK/ERK and PI3K/AKT pathways synergistically induced FOXO transcriptional activity and inhibited cell migration and capillary tube formation; these events were further enhanced in the presence of sulforaphane. Phosphorylation deficient mutants of FOXO enhanced antiangiogenic effects Of sulforaphane by activating the FOXO transcription factor. In conclusion, activation of FOXO transcription factor by sulforaphane could be an important physiological process to inhibit angiogenesis which may ultimately control tumor growth. These novel antiangiogenic activities of sulforaphane are likely to contribute to its cancer chemopreventive and therapeutic potential.