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

Abstract

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‐κB activity increase during progression of prostate cells toward greater tumorigenic potential. We have reported previously that physiological levels of zinc suppress NF‐κB 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‐κB 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‐κB and up‐regulates expression of the NF‐κB 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 IκBα dominant mutant adenovirus efficiently blocks expression of these cytokines in zinc deficient cells indicating that the observed effects are NF‐κB dependent. CONCLUSIONS Our findings suggest that zinc deficiency may contribute to the tumor progression via augmented expression of the NF‐κB‐dependent pro‐tumorigenic cytokines. Prostate 68: 1443–1449, 2008.