hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer

hZIP1 gene expression, ZIP1 transporter protein, and cellular zinc were prominent in normal peripheral zone glandular epithelium and in benign hyperplastic glands (also zinc accumulating glands). In contrast, hZIP1 gene expression and transporter protein were markedly down-regulated and zinc was depleted in adenocarcinomatous glands and in prostate intra-epithelial neoplastic foci (PIN). These changes occur early in malignancy and are sustained during its progression in the peripheral zone. hZIP1 is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1.The studies clearly establish that hZIP1 gene expression is down regulated and zinc is depleted in adenocarcinomatous glands. The fact that all the malignant cell lines express hZIP1 indicates that the down-regulation in adenocarcinomatous glands is likely due to in situ gene silencing. These observations, coupled with the numerous and consistent reports of loss of zinc accumulation in malignant cells in prostate cancer, lead to the plausible proposal that down regulation of hZIP1 is a critical early event in the development prostate cancer.Despite the extensive clinical and experimental studies over the recent decades, the pathogenesis of prostate cancer remains unknown. The genetic and molecular mechanisms responsible for and associated with the development of malignant prostate cells and their progression are largely unidentified [for reviews see [1,2]]. The major site for the development of prostate malignancy is the peripheral zone, which comprises about 70% of the prostate gland. It is well established that the normal peripheral zone has the function of accumulating extremely high zinc levels that are 3–10-fold greater than found in other soft tissues [3]. This capability resides in the highly specialized glandular secretory epithelial cells of the peripheral zone, which we characterize as "zinc-accumulating" cells. In contrast, the malignant prostate