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Carcinogenesis Advance Access published online on February 17, 2008
Carcinogenesis, doi:10.1093/carcin/bgn011
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Published by Oxford University Press 2008.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in cocultured reactive stromal cells

Xunxian Liu, Jeffrey D. Allen, Julia T. Arnold and Marc R. Blackman*

Endocrine Section, Laboratory of Clinical Investigation, Division of Intramural Research, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892

* To whom correspondence should be addressed. Tel: 202-745-8478; Fax: 202-518-4645; Email: Marc.Blackman{at}va.gov

Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. DHT stimulates IGF-I production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We cocultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose AR expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal cocultures, displayed a dose dependent increase in DNA fragmentation. NPE/6S cocultures exhibited reduced CM-induced cell-death with exposure to DHT, whereas NPE/PRSC cocultures exhibited CM-induced cell-death regardless of DHT treatment. DHT blocked CM-induced, IGF-I mediated, NPE death in cocultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell-death; decreased 6S cell IGF-I production by reducing AR and β-catenin nuclear localization; and inhibited IGF-I stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3β, and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.

Received September 11, 2007; revised January 3, 2008; accepted January 3, 2008.


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