Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer.
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.
Kong
Dejuan
D
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
Li
Yiwei
Y
Wang
Zhiwei
Z
Banerjee
Sanjeev
S
Sarkar
Fazlul H
FH
D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D004273:DNA, Neoplasm; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C016392:3,3'-diindolylmethane