Background: The genetic and molecular mechanisms responsible for and associated specifically with the development and progression of malignant prostate cells are largely unidentified. In addition, despite its implication in virtually all malignant cells, the role of altered cellular metabolism as an essential factor in prostate malignancy has been largely ignored. Moreover, the intermediary metabolism of normal prostate as well as malignant prostate cells is among the least studied and most poorly understood of all mammalian cells. Some important factors, especially the role of zinc, have been identified and implicated in the development and progression of prostrate malignancy. In this review, we provide a current and updated integrated assessment of the relationships of intermediary metabolism in normal prostate and in prostate cancer. The experimental and clinical evidence that leads to the formulation of concepts of normal and malignant prostate metabolism is presented. The evidence for a concept of zinc as a tumor suppressor agent and Zip1 zinc transporter as a tumor-suppressor gene is described.

This review emphasizes the importance and role of altered intermediary metabolism of prostate cells in the pathogenesis of prostate adenocarcinoma (PCa) and the progression of malignancy. The focus of the presentation is a summary of the overwhelming evidence which implicates the metabolic transformation of citrate-producing sane cells to citrate-oxidizing malignant cells in the process of malignancy. The evidence now demonstrates that altered zinc accumulation is an important factor in this transformation. These metabolic relationships are uniquely different from the metabolic alterations associated with tumorigenesis of other mammalian cells. The metabolic transformation of zinc-accumulating citrate-producing normal prostate epithelial cells to citrateoxidizing malignant cells has important implications on cellular bioenergetics, cell growth and apoptosis, lipogenesis, angiogenesis. Based on the metabolic considerations new concepts concerning the pathogenesis, diagnosis and treatment of prostate malignancy are presented. Unfortunately the metabolism of the prostate has been a seriously neglected and largely ignored area of prostate research. The importance of expanded research into the intermediary metabolism of normal and neoplastic prostate is essential to future significant advances in understanding and dealing with PCa. As an aside point, the reprint that I possess and treasure was personally inscripted and presented to me by Dr. Huggins over a decade ago. I was reminded that Dr. Huggins did present data that demonstrated that prostate tissue citrate levels were markedly decreased in prostate cancer. Although not emphasized by Dr. Huggins, to our knowledge this is the first report of the association of low citrate levels with prostate cancer. In our recent reviews and presentations we have credited the 1959 report of Cooper and Imfeld [24] as the first reported of this relationship. Cooper and Imfeld [24] did extend the earlier data of Huggins by the inclusion of normal prostate tissue analysis, and they directed specific attention to the significance of the low citrate values in prostate cancer. The pursuant report of Cooper and Farid [23] in 1964 provided the most comprehensive study at that time which substantiated the citrate relationships in normal prostate, BPH, and prostate cancer. Thus Huggins and his colleagues along with Cooper and colleagues share in the initial revelation of citrate relationships in prostate cancer. I regret the earlier omissions of the report of Dr. Huggins in some of our presentations. I should apologize in advance for any other early initial reports that I might have missed, and I would appreciate being advised of any corrections to this presentation.

Prostate epithelial cells possess a uniquely limiting mitochondrial (m-) aconitase activity that minimizes their ability to oxidize citrate. These cells also possess uniquely high cellular and mitochondrial zinc levels. Correlations among zinc, citrate, and m-aconitase in prostate indicated that zinc might be an inhibitor of prostate m-aconitase activity and citrate oxidation. The present studies reveal that zinc at near physiological levels inhibited m-aconitase activity of mitochondrial sonicate preparations obtained from rat ventral prostate epithelial cells. Corresponding studies conducted with mitochondrial sonicates of rat kidney cells revealed that zinc also inhibited the kidney m-aconitase activity. However the inhibitory effect of zinc was more sensitive with the prostate m-aconitase activity. Zinc inhibition fit the competitive inhibitor model. The inhibitory effect of zinc occurred only with citrate as substrate and was specific for the citrate 3 cis-aconitate reaction. Other cations (Ca 2؉ , Mn 2؉ , Cd 2؉) did not result in the inhibitory effects obtained with zinc. The presence of endogenous zinc inhibited the m-aconitase activity of the prostate mitochondrial preparations. Kidney preparations that contain lower endogenous zinc levels exhibited no endogenous inhibition of m-aconitase activity. Studies with pig prostate and seminal vesicle mitochondrial preparations also revealed that zinc was a competitive inhibitor against citrate of m-aconitase activity. The effects of zinc on purified beef heart m-aconitase verified the competitive inhibitor action of zinc. In contrast, zinc had no inhibitory effect on purified cytosolic aconitase. These studies reveal for the first time that zinc is a specific inhibitor of m-aconitase of mammalian cells. In prostate epithelial cells, in situ mitochondrial zinc levels inhibit m-aconitase activity, which provides a mechanism by which citrate oxidation is limited.Prostate secretory epithelial cells have the specialized function and capability of accumulating and secreting extraordinarily high levels of citrate. This is achieved by the existence of a uniquely limiting m-aconitase 1 activity that minimizes the oxidation of citrate via the Krebs cycle. Consequently, citrate synthesized by these cells is accumulated and secreted (which we refer to as "net citrate production"), thereby accounting for the extremely high (20 -150 mM) citrate content of human prostatic fluid. In typical mammalian cell metabolism, m-aconitase is not a regulatory, rate-limiting enzyme. Consequently, the steady-state citrate/isocitrate ratio of most cells is generally maintained at about 11/1, which is established by the aconitase equilibrium reaction, 88 citrate 7 4 cis-aconitate 7 8 isocitrate. In contrast, the citrate/isocitrate ratio in prostate is generally about 30/1. Also, the intracellular citrate concentration of prostate cells is estimated to be about 1.2 mM as compared with about 0.1-0.4 mM for typical mammalian cells. These and other relationships of prostate citrate metabolism an...

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The human prostate gland contains extremely high zinc levels; which is due to the specialized zinc-accumulating acinar epithelial of the peripheral zone. These cells evolved for their unique capability to produce and secrete extremely levels of citrate, which is achieved by the high cellular zinc level effects on the cell metabolism. This review highlights the specific functional and metabolic alterations that result from the accumulation of the high zinc levels, especially its effects on mitochondrial citrate metabolism and terminal oxidation. The implications of zinc in the development and progression of prostate cancer are described, which is the most consistent hallmark characteristic of prostate cancer. The requirement for decreased zinc resulting from down regulation of ZIP1 to prevent zinc cytotoxicity in the malignant cells is described as an essential early event in prostate oncogenesis. This provides the basis for the concept that an agent (such as the zinc ionophore, clioquinol) that facilitates zinc uptake and accumulation in ZIP1-deficient prostate tumors cells will markedly inhibit tumor growth. In the current absence of an efficacious chemotherapy for advanced prostate cancer, and for prevention of early development of malignancy; a zinc treatment regimen is a plausible approach that should be pursued.