Kong Dejuan, Li Yiwei, Wang Zhiwei, Banerjee Sanjeev, Sarkar Fazlul H
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
Cancer Res. 2007 Apr 1;67(7):3310-9. doi: 10.1158/0008-5472.CAN-06-4277.
Progression of prostate cancer is believed to be dependent on angiogenesis induced by tumor cells. 3,3'-Diindolylmethane (DIM) has been shown to repress neovascularization in a Matrigel plug assay and inhibit cell proliferation, migration, invasion, and capillary tube formation of cultured human umbilical vein endothelial cells. However, the molecular mechanism, by which DIM inhibits angiogenesis and invasion, has not been fully elucidated. Therefore, we sought to explore the molecular mechanism by which DIM inhibits angiogenesis and invasion, specifically by investigating the role of angiogenic factors secreted by prostate cancer cells which control all steps of angiogenesis. We found that BioResponse DIM (B-DIM), a formulated DIM with higher bioavailability, inhibited angiogenesis and invasion by reducing the bioavailability of vascular endothelial growth factor (VEGF) via repressing extracellular matrix-degrading proteases, such as matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA), in human prostate cancer cells and reduced vascularity (angiogenesis) in vivo using Matrigel plug assay. We also found that B-DIM treatment inhibited DNA binding activity of nuclear factor-kappaB (NF-kappaB), which is known to mediate the expression of many NF-kappaB downstream target genes, including VEGF, IL-8, uPA, and MMP-9, all of which are involved in angiogenesis, invasion, and metastasis. Our data suggest that inhibition of NF-kappaB DNA binding activity by B-DIM contributes to the regulated bioavailability of VEGF by MMP-9 and uPA and, in turn, inhibits invasion and angiogenesis, which could be mechanistically linked with the antitumor activity of B-DIM as observed previously by our laboratory in a prostate cancer animal model.
前列腺癌的进展被认为依赖于肿瘤细胞诱导的血管生成。3,3'-二吲哚甲烷（DIM）已在基质胶栓试验中显示出可抑制新生血管形成，并抑制培养的人脐静脉内皮细胞的增殖、迁移、侵袭和毛细血管管腔形成。然而，DIM抑制血管生成和侵袭的分子机制尚未完全阐明。因此，我们试图探索DIM抑制血管生成和侵袭的分子机制，特别是通过研究前列腺癌细胞分泌的血管生成因子在血管生成各个步骤中的作用来进行探索。我们发现，生物反应性DIM（B-DIM），一种具有更高生物利用度的配方DIM，通过抑制细胞外基质降解蛋白酶，如基质金属蛋白酶（MMP）-9和尿激酶型纤溶酶原激活剂（uPA），降低血管内皮生长因子（VEGF）的生物利用度，从而抑制人前列腺癌细胞中的血管生成和侵袭，并使用基质胶栓试验在体内减少血管形成（血管生成）。我们还发现，B-DIM处理可抑制核因子-κB（NF-κB）的DNA结合活性，已知NF-κB可介导许多NF-κB下游靶基因的表达，包括VEGF、白细胞介素-8、uPA和MMP-9，所有这些基因都参与血管生成、侵袭和转移。我们的数据表明，B-DIM对NF-κB DNA结合活性的抑制作用有助于通过MMP-9和uPA调节VEGF的生物利用度，进而抑制侵袭和血管生成，这可能与我们实验室之前在前列腺癌动物模型中观察到的B-DIM的抗肿瘤活性在机制上相关联。
