Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-κB-dependent pathway

BACKGROUND. Zinc accumulation diminishes early in the course of prostate malignancy and continues to decline during progression toward hormone-independent growth. In contrast, constitutive levels of NF-kappa B activity increase during progression of prostate cells toward greater tumorigenic potential. We have reported previously that physiological levels of zinc Suppress NF-kappa B activity in prostate cancer cells and reduce expression of pro-angiogenic and pro-metastatic cytokines VEGF, IL-6, IL-8, and MMP-9 associated with negative prognostic features in prostate cancer. METHODS. Intracellular zinc levels were examined by atomic absorption spectroscopy. NF-kappa B activity was examined by TransAm and Luciferase reporter assays, and Western blot analysis of p50 nuclear translocation. VEGF, IL-6 and IL-8 levels were assessed by ELISA. RESULTS. Selective zinc deficiency induced by the membrane-permeable zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) increases activation of NF-kappa B and up-regulates expression of the NF-kappa B controlled pro-angiogenic and pro-metastatic cytokines VEGF, IL-6 and IL-8 in androgen-independent PC-3 and DU-145 prostate cancer cells. Pre-incubation with I kappa B alpha dominant mutant adenovirus efficiently blocks expression of these cytokines in zinc deficient cells indicating that the observed effects are NF-kappa B dependent. CONCLUSIONS. Our findings suggest that zinc deficiency may contribute to the tumor progression via augmented expression of the NF-kappa B-dependent pro-tumorigenic cytokines.