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Nutrition and Disease

Soy Isoflavones Alter Expression of Genes Associated with Cancer Progression, Including Interleukin-8, in Androgen-Independent PC-3 Human Prostate Cancer Cells¹

Renita Handayani^*,2, Lori Rice^,2,3, Yuehua Cui^**, Theresa A. Medrano^*, Von G. Samedi^*, Henry V. Baker, Nancy J. Szabo and Kathleen T. Shiverick^*

Departments of ^* Pharmacology and Therapeutics, Surgery, Molecular Genetics and Microbiology, College of Medicine, Analytical Toxicology Core Laboratory, College of Veterinary Medicine, and ^** Department of Statistics, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL 32610

³ To whom correspondence should be addressed. E-mail: lrice{at}ufl.edu

ABSTRACT

High consumption of soy isoflavones in Asian diets has been correlated with a lower incidence of clinically important cases of prostate cancer. The chemopreventive properties of these diets may result from an interaction of several types of isoflavones, including genistein and daidzein. The present study investigated the effects of a soy isoflavone concentrate (ISF) on growth and gene expression profiles of PC-3 human prostate cancer cells. Trypan blue exclusion and [³H]-thymidine incorporation assays showed that ISF decreased cell viability and caused a dose-dependent inhibition of DNA synthesis, respectively, with 50% inhibition (IC₅₀) of DNA synthesis at 52 mg/L (P = 0.05). The glucoside conjugates of genistein and daidzein in ISF were converted to bioactive free aglycones in cell culture in association with the inhibition of DNA synthesis. Flow cytometry and Western immunoblot analyses showed that ISF at 200 mg/L caused an accumulation of cells in the G₂/M phase of the cell cycle (P < 0.05) and decreased cyclin A by 20% (P < 0.05), respectively. The effect of ISF on the gene expression profile of PC-3 cells was analyzed using Affymetrix oligonucleotide DNA microarrays that interrogate 17,000 human genes. Of the 75 genes altered by ISF, 28 were upregulated and 47 were downregulated (P < 0.05). Further analysis showed that IL-8, matrix metalloproteinase 13, inhibin ß A, follistatin, and fibronectin mRNA levels were significantly reduced, whereas the expression of p21^CIP1, a major cell cycle inhibitory protein, was increased. The effects of ISF on the expression of IL-8 and p21^CIP1 mRNA and protein were validated at high and low ISF concentrations. Our data show that ISF inhibits the growth of PC-3 cells through modulation of cell cycle progression and the expression of genes involved in cell cycle regulation, metastasis, and angiogenesis.

KEY WORDS: • interleukin-8 • isoflavones • microarray • p21^CIP1 • prostate

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