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

Department of Urological Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
The Prostate (Impact Factor: 3.57). 09/2008; 68(13):1443-9. DOI: 10.1002/pros.20810
Source: PubMed


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-kappaB activity increase during progression of prostate cells toward greater tumorigenic potential. We have reported previously that physiological levels of zinc suppress NF-kappaB 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.
Intracellular zinc levels were examined by atomic absorption spectroscopy. NF-kappaB 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.
Selective zinc deficiency induced by the membrane-permeable zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN) increases activation of NF-kappaB and up-regulates expression of the NF-kappaB 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 kappaB alpha dominant mutant adenovirus efficiently blocks expression of these cytokines in zinc deficient cells indicating that the observed effects are NF-kappaB dependent.
Our findings suggest that zinc deficiency may contribute to the tumor progression via augmented expression of the NF-kappaB-dependent pro-tumorigenic cytokines.

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