hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands

Abstract

Background: The normal human prostate glandular epithelium has the unique function of accumulating high levels of zinc. In prostate cancer this capability is lost as an early event in the development of the malignant cells. The mechanism and factors responsible for the ability of the normal epithelial cells to accumulate zinc and the loss of this capability in the malignant cells need to be identified. We previously reported that Zip1 is an important zinc uptake transporter in prostate cells and is down regulated in the malignant cells in situ along with the depletion of zinc levels. In this report we investigated the expression of two other Zip family zinc transporters, Zip2 and Zip3 in malignant versus nonmalignant (normal and BPH) glands. Zip2 and Zip3 relative protein levels were determined by immunohistochemistry analysis of human prostate tissue sections.

Results: Normal and BPH glandular epithelium consistently exhibited the strong presence of both Zip 2 and Zip3; whereas both transporters consistently were essentially non-detectable in the malignant glands. This represents the first report of the expression of Zip3 in human prostate tissue; and more importantly, reveals that ZiP2 and Zip3 are down regulated in malignant cells in situ as we also had demonstrated for Zip1. Zip2 and Zip3 transporter proteins were localized predominantly at the apical cell membrane, which is in contrast to the Zip1 localization at the basolateral membrane. Zip2 and Zip3 seemingly are associated with the re-uptake of zinc from prostatic fluid.

Conclusion: These results coupled with previous reports implicate Zip2 and Zip3 along with Zip1 as important zinc uptake transporters involved in the unique ability of prostate cells to accumulate high cellular zinc levels. Zip1 is important for the extraction of zinc from circulation as the primary source of cellular zinc. Zip 2 and Zip3 appear to be important for retention of the zinc in the cellular compartment. The down regulation of all three transporters in the malignant cells is consistent with the loss of zinc accumulation in these cells. Since zinc imposes tumor suppressor effects, the silencing of the gene expression for these transporters is a required event for the manifestation of the malignant activities of the neoplastic cells. This now provides new insights into the genetic/molecular events associated with the development of prostate cancer; and supports our concept of Zip1, and now Zip2 and Zip3, as tumor suppressor genes and zinc as a tumor suppressor agent.

Figure 1

Immunohistochemical detection of Zip2 transporter protein in normal, BPH and malignant sections of representative prostate tissues. Note the immuno-positivity of the apical plasma membrane of normal and BPH glands (black arrows). The malignant glands show no detectable Zip2 membrane immunoreactivety (red arrows).

Figure 2

Immunohistochemical detection of Zip3 transporter protein in normal, BPH and malignant sections of representative prostate tissues. (top; magnifications are ×400). Note the immuno-positivity of the apical plasma membrane of normal and BPH glands (black arrow). The malignant glands show no detectable Zip3 membrane immunoreactivety (red arrows).

Figure 3

Comparative localization of Zip1, Zip2, and Zip3 in prostate glands. The black arrows point to the immunopositive staining at the apical membrane. The blue arrows point to the immunopositive staining at the basoloateral membrane.