A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer

Abstract

The human prostate gland contains extremely high zinc levels; which is due to the specialized zinc-accumulating acinar epithelial of the peripheral zone. These cells evolved for their unique capability to produce and secrete extremely levels of citrate, which is achieved by the high cellular zinc level effects on the cell metabolism. This review highlights the specific functional and metabolic alterations that result from the accumulation of the high zinc levels, especially its effects on mitochondrial citrate metabolism and terminal oxidation. The implications of zinc in the development and progression of prostate cancer are described, which is the most consistent hallmark characteristic of prostate cancer. The requirement for decreased zinc resulting from down regulation of ZIP1 to prevent zinc cytotoxicity in the malignant cells is described as an essential early event in prostate oncogenesis. This provides the basis for the concept that an agent (such as the zinc ionophore, clioquinol) that facilitates zinc uptake and accumulation in ZIP1-deficient prostate tumors cells will markedly inhibit tumor growth. In the current absence of an efficacious chemotherapy for advanced prostate cancer, and for prevention of early development of malignancy; a zinc treatment regimen is a plausible approach that should be pursued.

Keywords: Citrate metabolism; Prostate; Prostate cancer; ZIP1-deficient prostate malignancy; Zinc effects and cytotoxicity; Zinc treatment.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Fig. 1

In situ zinc dithizone staining of normal and malignant peripheral zone. Note the prominent zinc staining in the normal acini epithelium compared to lower zinc in the stroma. The malignant cells exhibit low zinc staining.

Fig. 2

Identification of the metabolic alterations in the specialized citrate-producing normal prostate cells compared to the typical citrate metabolism in most mammalian cells. Blue represents key transporters and enzymes required for citrate production and secretion. PDH = pyruvate dehydrogenase; MAAT = mitochondria aspartate aminotransferase; CS = citrate synthase; acon = aconitase; CTP = citrate transport protein.

Fig. 3

The m-aconitase reaction and its inhibition by zinc. CS = citrate synthase; IDH = isocit dehydrogenase.

Fig. 4

The kinetics of normal prostate epithelial cell mitochondrial uptake of zinc from ZnLigands. A. Zinc uptake rate from ZnLigands containing 20 μM Zn, showing that the Zn uptake depends on total exchangeable zinc and is independent of the free Zn++ concentration. B. Michaelis-Menton uptake kinetics. C. Lineweaver-Burk plot of B. (Taken from Ref. [10]).

Fig. 5

Inhibition of succinate-stimulated respiration of prostate and liver cell mitochondria by ZnLigands. All ZnLigands contained 20 μM Zn. (Taken from Ref. [10]).

Fig. 6

Zinc effects on electron transport of prostate and liver cell mitochondria. All ZnLigands contained 20 μM Zn (Taken from Ref. [10]).

Fig. 7

ZIP1 transporter in prostate cells and its role in zinc uptake. A. Immunohistochemistry of normal human prostate tissue section showing ZIP1 localization at the plasma membrane of the normal acinar epithelium. B. Shows that wildtype PC-3 cells exhibit plasma membrane localized ZIP1 transporter. C. Shows that the uptake of zinc by PC-3 wildtype is increased in ZIP1 over-expressed cells; and is decreased in ZIP1-mutated cells. (7A, B taken from Refs. [30];7C taken from Ref. [55].

Fig. 8

In situ identification of the status of zinc and ZIP1 in tissue sections of normal and malignant prostate. A. Shows zinc staining identifying high zinc (yellow stain) in the normal acinar epithelium versus low zinc (red stain) in malignancy. B. Shows prominent plasma membrane localized ZIP1 in the normal epithelium; and absence of ZIP1 in malignancy. C. Shows high gene expression (green) in the normal acinar epithelium; and the absence of gene expression (red) in malignancy. (Taken from Ref. [30].

Fig. 9

The concept of the genetic/metabolic transformation in the oncogenic development of malignancy in cancer; and the implications of ZIP1/Zn down regulation in prostate cancer. A. The oncogenic initiation of the transformation of the normal cell to the neoplastic cell, and its progression to premalignancy and the development of malignancy. B. RREB-1 as a negative regulator of ZIP1gene expression, and its upregulation during the transformation of the neoplastic cell to the premalignant cell, so as to silence ZIP1 expression and prevent cytotoxic zinc accumulation in the progression to malignancy. (PIN = prostate intraepithelial neoplasia premalignant lesion).

Fig. 10

Immunohistochemistry effects of REEB-1 regulation on ZIP1 transporter abundance in PC-3 cells. A. shows the down regulation of RREB-1 increases ZIP1 abundance. B. Shows that increased RREB-1 decreases ZIP1 abundance. (Taken from Refs. [47]).

Fig. 11

RREB-1 and ZIP1 abundance in normal versus prostate cancer tissue sections. Immunohistochemistry shows increased RREB-1 and loss of plasma membrane ZIP1 transporter in malignant acini. (Taken from Ref. [47]).

Fig. 12

A. Effects of zinc treatment on PC-3 tumor growth in xenograft mice. B. Zinc and citrate levels in the resected tumor tissues. C. Bax and Bcl-2 levels in the resected tumors. D. Tunel assay for apoptosis in tumors. (Taken from Ref. [59]).

Fig. 13

Effects of clioquinol treatment on PC-3 ZIP1-deficient tumor growth in the mouse xenograft animals. A. Shows the tumor growth rates during the treatment period. B. Shows the total tumor growth at the end of the treatment period. (Modified from Refs. [62,63]).