Prostate cancer (PCa) is the second leading cause of cancer deaths in males. The diagnosis, treatment, and prevention of PCa are important contemporary issues. New approaches are required to address this major health problem. Important fundamental information and understanding of the pathogenesis and progression are seriously lacking; which contributes to the slow progress in addressing these issues. Compelling evidence now implicates the involvement of altered zinc accumulation and citrate-related metabolism in the pathogenesis and progression of PCa. The most consistent hallmark characteristic of PCa is the inability of the malignant cells to accumulate zinc and citrate as contrasted with the extremely high accumulation of zinc and citrate associated with normal prostate and benign prostatic hyperplasia (BPH). The consistency of this metabolic change is revealed by the fact that in situ MRS determination of prostate citrate levels now provides the most accurate and sensitive test for the detection and localization of malignancy. The key reaction in the metabolic transformation of non-malignant citrate-producing prostate epithelial cells to citrate-oxidizing malignant cells is mitochondrial (m-) aconitase. The expression and level of m-aconitase are regulated by hormones (testosterone and prolactin) and by zinc specifically in prostate cells. In this application, the mechanism and specificity of hormonal regulation of the m-aconitase gene in normal and malignant prostate cells will be established. The role of zinc in modulating the activity and equilibrium of m-aconitase will be investigated. The studies will be performed with normal fresh prostate epithelial cells obtained from rat prostate tissue; and with human malignant prostate cell lines. The long-term objectives are to understand the unique metabolic relationships associated with the alteration of citrate-related metabolism of normal and malignant prostate cells; to establish the role of zinc and hormones in this altered metabolism, and the implications in the pathogenesis and progression of malignancy. This information will provide new approaches to the diagnosis, prevention, and treatment of PCa.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071207-08
Application #
6686436
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1996-06-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2005-11-30
Support Year
8
Fiscal Year
2004
Total Cost
$246,510
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Franklin, Renty B; Zou, Jing; Zheng, Yao et al. (2016) Zinc Ionophore (Clioquinol) Inhibition of Human ZIP1-Deficient Prostate Tumor Growth in the Mouse Ectopic Xenograft Model: A Zinc Approach for the Efficacious Treatment of Prostate Cancer. Int J Cancer Clin Res 3:
Costello, Leslie C; Franklin, Renty B; Reynolds, Mark A et al. (2012) The Important Role of Osteoblasts and Citrate Production in Bone Formation: ""Osteoblast Citration"" as a New Concept for an Old Relationship. Open Bone J 4:
Costello, Leslie C; Zou, Jing; Desouki, Mohamed Mokhtar et al. (2012) Evidence for changes in RREB-1, ZIP3, and Zinc in the early development of pancreatic adenocarcinoma. J Gastrointest Cancer 43:570-8
Franklin, Renty B; Levy, Bernard A; Zou, Jing et al. (2012) ZIP14 zinc transporter downregulation and zinc depletion in the development and progression of hepatocellular cancer. J Gastrointest Cancer 43:249-57
Costello, Leslie C; Franklin, Renty B (2012) Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity. Expert Rev Anticancer Ther 12:121-8
Costello, Leslie C; Franklin, Renty B (2011) Integration of molecular genetics and proteomics with cell metabolism: how to proceed; how not to proceed! Gene 486:88-93
Costello, Leslie C; Franklin, Renty B (2011) Zinc is decreased in prostate cancer: an established relationship of prostate cancer! J Biol Inorg Chem 16:3-8
Costello, Leslie C; Fenselau, Catherine C; Franklin, Renty B (2011) Evidence for operation of the direct zinc ligand exchange mechanism for trafficking, transport, and reactivity of zinc in mammalian cells. J Inorg Biochem 105:589-99
Franklin, Renty B; Costello, Leslie C (2009) The important role of the apoptotic effects of zinc in the development of cancers. J Cell Biochem 106:750-7
Pal, Robert; Parker, David; Costello, Leslie C (2009) A europium luminescence assay of lactate and citrate in biological fluids. Org Biomol Chem 7:1525-8

Showing the most recent 10 out of 38 publications