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Carcinogenesis Advance Access published online on April 10, 2006
Carcinogenesis, doi:10.1093/carcin/bgl034
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received November 10, 2005
Revised February 21, 2006
Accepted March 27, 2006

CANCER BIOLOGY

Diverse effects of zinc on NF-{kappa}B and AP-1 transcription factors: implications for prostate cancer progression

Robert G. Uzzo 1, Paul L. Crispen 1, Konstantin Golovine 1, Peter Makhov 1, Eric M. Horwitz 1, and Vladimir M. Kolenko 1 *

1 Department of Urological Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA

* To whom correspondence should be addressed.
Vladimir M. Kolenko, E-mail: Vladimir.Kolenko{at}fccc.edu


  Abstract

NF-{kappa}B and AP-1 nuclear transcriptional factors regulate expression of multiple genes involved in tumor growth, metastasis, and angiogenesis; however, the relative contribution of each factor to cancer initiation and progression has not been established. Prostate carcinogenesis involves transformation of normal zinc-accumulating epithelial cells to malignant cells which do not accumulate zinc. Whereas activation of both NF-{kappa}B and AP-1 has been implicated in prostate cancer development and growth, we tested the relative effects of zinc supplementation on these important transcriptional factors. Herein, we demonstrate that physiological levels of zinc inhibit NF-{kappa}B but augment activities of AP-1 in DU-145 and PC-3 human prostate cancer cells. Additionally, we show that chelation of zinc with membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) abolishes this effect. We further propose a potential mechanism for this observation by demonstrating that zinc supplementation induces phosphorylation of the members of three major MAPK subfamilies regulating AP-1 and NF-{kappa}B activation (Erk 1/2, JNK, and p38) while blocking TNF-{alpha}-mediated degradation of the inhibitory subunit I{kappa}B{alpha} and nuclear translocation of RelA in prostate cancer cells. VEGF, IL-6, IL-8, and MMP-9 are major pro-angiogenic and pro-metastatic molecules whose promoter regions contain binding sites for both NF-{kappa}B and AP-1. These cytokines have been associated with negative prognostic features in prostate cancer. We demonstrate that treatment of human prostate cancer cell lines with zinc reduces expression of VEGF, IL-6, IL-8, and MMP-9. We further show that zinc reduces expression of intercellular adhesion molecule-1 (ICAM-1) and functionally suppresses tumor cell invasiveness and adhesion. Therefore, the ability of zinc supplementation to inhibit NF-{kappa}B supercedes zinc-mediated activation of AP-1 family members. Up-regulation of intracellular zinc levels may have important implications for inhibiting the angiogenic and metastatic potentials of malignant cells, predominantly through suppression of NF-{kappa}B signaling.

Keywords: prostate; NF-{kappa}B; AP-1; zinc; invasiveness; adhesion.
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