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Carcinogenesis Advance Access published online on April 29, 2007
Carcinogenesis, doi:10.1093/carcin/bgm103
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Akt/GSK3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression towards a poorly differentiated phenotype

Lara H. El Touny and Partha P. Banerjee

Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, District of Columbia

Address all correspondence and request for reprints to: Partha P. Banerjee, Department of Biochemistry, Molecular and Cellular Biology, Medical-Dental Building, Room C-406B, 3900 Reservoir Road, NW, Washington DC 20057, USA. E-mail: ppb{at}georgetown.edu; Phone: (202)-687-8611; Fax: (202)-687-1823.

Anti-proliferative properties of genistein in prostate and other cancers have been studied extensively. However, the identification of genistein targets that may mediate its chemopreventive effects in vivo requires further elucidation. In this study, we have demonstrated that the incorporation of genistein in the diet of TRAMP/FVB mice resulted in a reduction in prostate size and the incidence of poorly differentiated cancer ensuing in an accumulation of prostates at the prostatic intraepithelial neoplasia (PIN) stage. TRAMP/FVB prostate cancer progression and the onset of poorly differentiated cancer were characterized by the activation of Akt, phosphorylation of GSK-3ß, post-transcriptional upregulation of cyclin D1 and repression of cadherin-1 via snail-1 upregulation. Incorporation of genistein in the diet, significantly inhibited the activation of Akt, restored the activation of GSK-3ß, reduced cyclin D1 levels post-transcriptionally, and maintained the expression of the cadherin-1 complex via downregulation of snail-1. By identifying the Akt-GSK-3 pathway, and subsequently its downstream effectors, as targets for genistein chemopreventive action, we have elucidated one possible mechanism by which genistein decreases the proliferative potential, retards cancer progression and maintains the integrity of the prostatic epithelial cells in vivo.

Key Words: Genistein • TRAMP/FVB • Akt • GSK-3 • Snail-1

Received February 16, 2007; revised April 5, 2007; accepted April 19, 2007.


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