Inhibition of growth factor-induced Ras signaling in vascular endothelial cells and angiogenesis by 3,3′-diindolylmethane
Inhibition of growth factor-induced Ras signaling in vascular endothelial cells and angiogenesis by 3,3′-diindolylmethane
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DOI：
10.1093/carcin/bgi230
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发表时间：
2006-03-01
期刊：
影响因子：
4.7
通讯作者：
Bjeldanes, LF
中科院分区：
文献类型：
--
作者：
Chang, XF;Firestone, GL;Bjeldanes, LF
3，3 '-二吲哚基甲烷（DIM）是食用花椰菜和其他十字花科蔬菜时产生的吲哚衍生物，已显示在体内和体外模型中具有多种抗癌作用。本研究旨在阐明DIM抗血管生成的作用机制。我们发现DIM可以抑制血管内皮生长因子（VEGF）诱导的人脐血管内皮细胞（HUVEC）细胞增殖和DNA合成。与这种抑制一致，VEGF诱导的细胞外信号调节激酶（ERK 1/2）磷酸化大大减少。然而，VEGF诱导的VEGF受体磷酸化不受DIM的影响，表明DIM对该受体的酪氨酸激酶活性不产生直接和特异性影响。进一步的研究表明，DIM对多种生长因子诱导的ERK 1/2磷酸化具有相似的抑制作用。此外，Ras-GTP含量，这显着增加后，HUVEC的挑战，无论是个别的生长因子或血清，减少了约80%，与25 μ M的DIM处理，这反过来又导致Raf和MEK的活性降低，最终在ERK 1/2激活的下降。在HUVECs中过表达具有组成性活性的GT3突变体Ras G1/2 V，可逆转DIM对ERK 1/2激活的抑制作用。在啮齿动物基质胶塞模型中，DIM的存在强烈减少VEGF诱导的新血管形成，表明DIM在体内是活性的。这些数据提供了证据表明，DIM抑制由VEGF和其他生长因子诱导的Ras信号传导，这干扰了血管生成所必需的下游生物学效应。
3,3'-Diindolylmethane (DIM), an indole derivative produced on consumption of broccoli and other cruciferous vegetables, has been shown to have multiple anticancer effects in both in vivo and in vitro models. The present study was carried out to clarify the mechanism of DIM's antiangiogenic activity. We found that DIM can inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation and DNA synthesis in human umbilical vascular endothelial cells (HUVECs). Consistent with this inhibition, VEGF-induced extracellular signal-regulated kinase (ERK1/2) phosphorylation was greatly reduced. However, VEGF receptor phosphorylation induced by VEGF was not affected by DIM, indicating that DIM does not exert a direct and specific effect on the tyrosine kinase activity of this receptor. Further studies showed that DIM had a similar inhibitory effect on ERK1/2 phosphorylation induced by a variety of growth factors. Furthermore, Ras-GTP content, which dramatically increased after HUVECs were challenged by either individual growth factors or serum, was reduced by similar to 80% with 25 mu M DIM treatment, which in turn resulted in the reduced activities of Raf and MEK, culminating in the drop of ERK1/2 activation. Overexpression of constitutively active GTPase mutant, Ras G12V, in HUVECs reversed the inhibitory effect of DIM on ERK1/2 activation. In a rodent Matrigel plug model, the presence of DIM strongly reduced VEGF-induced neovascularization, indicating that DIM is active in vivo. These data provide evidence that DIM inhibits Ras signaling induced by VEGF and other growth factors, which interferes with its downstream biological effects necessary for angiogenesis.