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

Franklin, Feng Pei, Milon B, Desouki, Singh, Kajdacsy-Balla André, Bagasra Omar, Costello

Description

The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. The lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1) as an important zinc transporter involved in zinc accumulation in prostate cells. Therefore, we investigated the possibility that down-regulation of hZIP1 gene expression might be involved in the inability of malignant prostate cells to accumulate zinc. To address this issue, the expression of hZIP1 and the depletion of zinc in malignant versus non-malignant prostate glands of prostate cancer tissue sections were analyzed. hZIP1 expression was also determined in malignant prostate cell lines. Results 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. h ZIP1 is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1. Conclusion 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.

Sujets

• Prostate cancer
• Zinc
• Citrate

Informations

• Publié par: biomed
• Publié le: 01 janvier 2005
• Nombre de lectures: 76
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Molecular Cancer

BioMedCentral

Open Access Research hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer 1 11 2 Renty B Franklin*, Pei Feng, B Milon, Mohamed M Desouki, 2 34 Keshav K Singh, André KajdacsyBalla, Omar Bagasraand 1 Leslie C Costello

1 2 Address: Departmentof Biomedical Sciences, Dental School. University of Maryland, Baltimore, Md, USA,Department of Cancer Genetics, 3 4 Roswell Park Cancer Institute, Buffalo, NY, USA,Department of Pathology, University of Illinois, Chicago, IL, USA andDepartment of Biology; South Carolina Center for Biotechnology; Claflin University, Orangeburg, SC, USA Email: Renty B Franklin*  [e-mail]; Pei Feng  [e-mail]; B Milon  [e-mail]; Mohamed M Desouki  [e-mail]; Keshav K Singh  [e-mail]; André KajdacsyBalla  [e-mail]; Omar Bagasra  [e-mail]; Leslie C Costello  [e-mail] * Corresponding author

Published: 09 September 2005Received: 14 April 2005 Accepted: 09 September 2005 Molecular Cancer2005,4:32 doi:10.1186/1476-4598-4-32 This article is available from: http://www.molecular-cancer.com/content/4/1/32 © 2005 Franklin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

prostate cancerzincZIP1 zinc transportercitrateZIP1 gene expression

Abstract Background:The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. The lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1) as an important zinc transporter involved in zinc accumulation in prostate cells. Therefore, we investigated the possibility that down-regulation ofhZIP1gene expression might be involved in the inability of malignant prostate cells to accumulate zinc. To address this issue, the expression ofhZIP1and the depletion of zinc in malignant versus non-malignant prostate glands of prostate cancer tissue sections were analyzed.hZIP1expression was also determined in malignant prostate cell lines. Results:hZIP1gene 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,hZIP1gene 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. hZIP1is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1. Conclusion:The studies clearly establish thathZIP1gene expression is down regulated and zinc is depleted in adenocarcinomatous glands. The fact that all the malignant cell lines expresshZIP1indicates 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 ofhZIP1is a critical early event in the development prostate cancer.

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