TY - JOUR
T1 - Overexpression of the zinc uptake transporter hZIP1 inhibits nuclear factor-κB and reduces the malignant potential of prostate cancer cells in vitro and in vivo
AU - Golovine, Konstantin
AU - Makhov, Peter
AU - Uzzo, Robert G.
AU - Shaw, Tavis
AU - Kunkle, David
AU - Kolenko, Vladimir M.
PY - 2008
Y1 - 2008
N2 - Purpose: Intracellular zinclevels and expression of the zincuptake transporter, hZIP1, are markedly down-regulated in prostate adenocarcinomatous tissue compared with normal prostate tissue. Our previous studies have shown that zincinhibits nuclear factor-κB(NF-κB) 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-κB activity and tumorigenic potential in human prostate cancer cells in vitro and in vivo. Experimental Design: NF-κB 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-κB activity in the presence of physiologic levels of zinc. NF-κB inhibition coincides with a reduction in expression of several NF-κB 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-κB-dependent pathways and support the concept that hZIP1 may function as a tumor suppressor gene in prostate cancer.
AB - Purpose: Intracellular zinclevels and expression of the zincuptake transporter, hZIP1, are markedly down-regulated in prostate adenocarcinomatous tissue compared with normal prostate tissue. Our previous studies have shown that zincinhibits nuclear factor-κB(NF-κB) 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-κB activity and tumorigenic potential in human prostate cancer cells in vitro and in vivo. Experimental Design: NF-κB 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-κB activity in the presence of physiologic levels of zinc. NF-κB inhibition coincides with a reduction in expression of several NF-κB 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-κB-dependent pathways and support the concept that hZIP1 may function as a tumor suppressor gene in prostate cancer.
KW - Animals
KW - Cation Transport Proteins/genetics
KW - Cell Line, Tumor
KW - Genes, Tumor Suppressor
KW - Humans
KW - Male
KW - Mice
KW - NF-kappa B/antagonists & inhibitors
KW - Neoplasm Invasiveness
KW - Neoplasm Transplantation
KW - Prostatic Neoplasms/metabolism
KW - Transfection
UR - http://www.scopus.com/inward/record.url?scp=53049083485&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-08-0455
DO - 10.1158/1078-0432.CCR-08-0455
M3 - Article
C2 - 18765529
SN - 1078-0432
VL - 14
SP - 5376
EP - 5384
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -