title: Suppression of VEGF-mediated autocrine and paracrine interactions between prostate cancer cells and vascular endothelial cells by soy isoflavones.
abstract: Angiogenesis is an essential process involved in the development and progression of prostate cancer. Vascular endothelial growth factor (VEGF) is hypothesized to be a critical regulator of angiogenesis during prostate carcinogenesis. We have reported that dietary soy products inhibit prostate tumor progression in animal models, in association with a reduction in tumor microvessel density. The goal of the present study is to investigate potential antiangiogenic mechanisms of genistein, the major soy isoflavone, using in vitro systems. Genistein (5-50 muM) significantly inhibited the growth of human umbilical vein endothelial cells (HUVECs) in control media when stimulated by supplemental VEGF or when cultured in hypoxia-exposed PC-3 prostate adenocarcinoma cell conditioned media. These in vitro studies suggest detectable inhibitory effects by 5-10 muM genistein (P<.05) with an IC(50) of approximately 20 muM or less. Genistein (10-50 muM) caused significant inhibition of basal VEGF expression and hypoxia-stimulated VEGF expression in both human prostate cancer PC-3 cells and HUVECs based on semiquantitative reverse transcription-polymerase chain reaction (P<.05). In parallel, VEGF secretion by PC-3 cells quantitated by enzyme-linked immunosorbent assay was significantly (P<.05) reduced by genistein (10-50 muM). Furthermore, genistein (10-50 muM) significantly (P<.05) reduced PC-3 nuclear accumulation of hypoxia-inducible factor-1alpha, the principle transcription factor that regulates VEGF expression in response to hypoxia. Expression of the VEGF receptor fms-like tyrosine kinase-1, but not kinase insert domain-containing kinase, in HUVECs was also reduced (P<.05) by genistein (10-50 muM). These observations support the hypothesis that genistein may inhibit prostate tumor angiogenesis through the suppression of VEGF-mediated autocrine and paracrine signaling pathways between tumor cells and vascular endothelial cells.
authors.affiliation: Comprehensive Cancer Center, Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Guo
authors.forename: Shihua
authors.initials: S
authors.lastname: Wang
authors.forename: Dahlys R
authors.initials: DR
authors.lastname: Hoot
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
mesh_terms: D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011471:Prostatic Neoplasms; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045730:Soy Foods; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: D017931:DNA Primers; D007529:Isoflavones; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D019833:Genistein; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2