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Overexpression of the Zinc Uptake Transporter hZIP1 Inhibits Nuclear Factor-B and Reduces the Malignant Potential of Prostate Cancer Cells In vitro and In vivo

Authors' Affiliation: Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Vladimir M. Kolenko, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-5620; Fax: 215-728-4333; E-mail: Vladimir.Kolenko{at}fccc.edu.

Purpose: Intracellular zinc levels and expression of the zinc uptake transporter, hZIP1, are markedly down-regulated in prostate adenocarcinomatous tissue compared with normal prostate tissue. Our previous studies have shown that zinc inhibits nuclear factor-B (NF-B) activity and reduces the malignant potential of prostate cancer cells in vitro. In this study, we investigate the functional effect of hZIP1 overexpression on NF-B activity and tumorigenic potential in human prostate cancer cells in vitro and in vivo.

Experimental Design: NF-B activity in PC-3 prostate cancer cells was examined by Western blotting and luciferase assay. ELISA was used to examine the expression of tumorigenic cytokines. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, adhesion, and invasiveness assays were used to assess the malignant potential of tumor cells. The effect of hZIP1 overexpression on prostate tumor progression in vivo was assessed using a xenograft model.

Results: Overexpression of the hZIP1 transporter in PC-3 cells results in significant inhibition of NF-B activity in the presence of physiologic levels of zinc. NF-B inhibition coincides with a reduction in expression of several NF-B controlled prometastatic and antiapoptotic factors as well as sensitization of the cells to etoposide and tumor necrosis factor-mediated apoptosis-inducing ligand-mediated cell death. Moreover, overexpression of the hZIP1 transporter induces regression of prostate tumor growth in a xenograft model.

Conclusions: Our results show that hZIP1 overexpression has a functional effect on the malignant potential of prostate cancer cells via inhibition of NF-B-dependent pathways and support the concept that hZIP1 may function as a tumor suppressor gene in prostate cancer.