Zinc and zinc transporters in normal prostate and the pathogenesis of prostate cancer

Abstract

Zinc is an essential metal for all cells. It plays a role in a wide variety of physiological and biochemical processes. In the prostate epithelial cell the accumulation of high cellular zinc is a specialized function that is necessary for these cells to carry out the major physiological functions of production and secretion of citrate. The production of citrate and its secretion into prostatic fluid is a differentiated function of the prostate epithelial cells that is apparently important for reproduction. The loss of citrate and zinc accumulation is the most consistent and persistent characteristic of prostate malignancy. This characteristic of prostate cancer indicates that the lost ability of the malignant cells to accumulate zinc and citrate is an important factor in the development and progression of malignancy. The lost ability of the epithelial cells to accumulate zinc and thus to also accumulate citrate is the result of decreased expression of specific zinc uptake transporters. The purpose of this presentation is to review the current understanding of zinc and zinc homeostasis in the prostate and the role of zinc and zinc transporters in the normal function of the prostate and the pathogenesis of prostate cancer.

FIGURE 1

The Distribution of Zinc in Prostate Epithelial Cells. Free Zn++ ions are virtually absent in the represented compartments. Abbreviations are: MT=Metallo-: LMW=low molecular weight; MZUT=mitochondrial zinc uptake transporter

FIGURE 2

Zinc Trafficking and Transport Into Mitochondria. 1. Zinc exists in interstitial fluid in a mobile ligand form. Zinc is donated from the ligand to Zip1 and transported across the plasma membrane into the cell where it is bound to a cytosolic ligand. 2. The mobile cytosolic zinc ligand permeates the mitochondrial outer membrane and enters the intermembrane space. 3. At the inner membrane, zinc is donated from the ligand to MZUT and transported into the matrix where it associates with mitochondrial ligands. MZUT= mitochondrial zinc uptake transporter.

FIGURE 3

Concept of ZIP Transport of Zinc. This concept depicts the transport of zinc in the absence of free Zn++ ions in the interstitial fluid. Zinc is passed from extracellular ligand to Zip transporter to intracellular ligand.

FIGURE 4

The Pathway of Net Citrate Production in Prostate Epithelial Cells. A major effect of intramitochondrial zinc is the inhibition of m-aconitase activity and thus citrate oxidation. Inhibition of citrate oxidation makes citrate available for secretion to prostatic fluid.

FIGURE 5

Zinc Induction of Mitochondrial Apoptogenesis in Prostate Cells. Zinc increases cellular Bax levels by increasing gene transcription (1) and/or post-transcriptional biosynthesis (2). Zinc facilitates the translocation of Bax to the mitochondria (3). Zinc facilitates Bax pore formation (4). Cytochrome c effluxes to cytosol and activates the caspase cascade (5) that leads to apoptosis.

FIGURE 6

Comparison of the zinc and citrate changes in prostate cancer. The citrate data are taken from Liney et al. (66). The values were determined by in situ MRS measurements. The normal and cancer citrate values are for the peripheral zone; and the adenoma values are for the central zone. The zinc data are from Zaichick et al. (67). The values were determined by analysis of biopsy.

FIGURE 7

The Concept of Zinc in the pathogenesis of prostate malignancy. The normal glandular epithelial cell expresses ZIP1 that permits zinc accumulation, which inhibits citrate oxidation and terminal respiration. A genetic transformation results in a neoplastic cell with potential malignant capability. ZIP1 expression is down-regulated, which eliminates Zip1 transporter and accumulation of zinc in the premalignant cell. The level of cellular zinc decreases which removes the inhibitory effects on citrate oxidation and terminal oxidation. The malignant cell is metabolically and bioenergetically capable of manifesting its malignant potential. Also, the apoptogenic effect of zinc is removed, which allows growth and progression of the malignant cell.