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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Our findings suggest that zinc deficiency may contribute to the tumor progression via augmented expression of the NF-kappaB-dependent pro-tumorigenic cytokines.
Golovine
Konstantin
K
Department of Urological Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Uzzo
Robert G
RG
Makhov
Peter
P
Crispen
Paul L
PL
Kunkle
David
D
Kolenko
Vladimir M
VM
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D027682:Cation Transport Proteins; D002614:Chelating Agents; D005029:Ethylenediamines; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C403517:SLC39A1 protein, human; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine