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Overexpression Of Zinc Uptake Transporter, hZIP1, Inhibits NF-κB Activity And Suppresses Tumorigenicity In Prostate Cancer Cells
Jason Rothman1, Peter Makhov2, Konstantin Golovine2, Robert G. Uzzo2, Vladimir Kolenko2
1Temple University Hospital, Philadelphia, PA;2Fox Chase Cancer Center, Philadelphia, PA
Introduction:
Zinc levels and expression of the zinc uptake transporter, hZIP1, are markedly down-regulated in prostate adenocarcinoma compared to normal glandular epithelium. Recent studies show a strong association between the development of prostate cancer and down-regulation of the hZIP1 transporter. Here we demonstrate that overexpression of the hZIP1 transporter in PC-3 prostate cancer cells results in significant inhibition of NF-κB activity in the presence of physiological levels of zinc and impact the expression of prometastatic proteins.
Methods:
Parental and hZIP1 transfected PC-3 cells were incubated with physiological levels of zinc. Intracellular free and total zinc levels were measured using Flouzin-3 staining followed by FACS analysis and atomic absorption spectrometry, respectively. TUNEL assay was used to measure apoptosis. NF-κB dependent proteins were measured by ELISA and Western blotting. Surface expression of ICAM-1 was determined by flow cytometry after cell staining.
Results:
PC-3 cells overexpressing hZIP1 exhibit reduced adhesion and expression of the intercellular adhesion molecule-1 (ICAM-1). NF-κB inhibition also coincided with reduced expression of NF-κB controlled pro-metastatic proteins, IL-6 and IL-8, and anti-apoptotic proteins, Bcl-2, Bcl-XL and XIAP. Pre-incubation of hZIP1 transfectants with physiological levels of zinc sensitized tumor cells to etoposide and TRAIL mediated cell death.
Conclusions:
These results support a critical role of the hZIP1 gene in the development and progression of prostatic malignancies and demonstrate that modulation of intracellular zinc levels may have important implications for inhibiting the malignant behavior of tumor cells, predominantly through suppression of NF-κB signaling.
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