Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer

  title={Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer},
  author={Lc Costello and Renty B. Franklin},
  journal={The Prostate},
The prostate gland of humans and many other animals has the major function of accumulating and secreting extraordinarily high levels of citrate. This specialized metabolic process of “net citrate production” is the result of unique metabolic capabilities of the secretory epithelial cells. Most importantly, in prostate cancer (Pca) the capability for net citrate production is lost. In addition to citrate, the normal and BPH (benign prostatic hyperplasia) prostate also accumulates the highest… 


The purpose of this presentation is to review the current understanding of zinc and zinc homeostasis in the prostate and the role of zincand zinc transporters in the normal function of the prostateand the pathogenesis of prostate cancer.

The Intermediary Metabolism of the Prostate: A Key to Understanding the Pathogenesis and Progression of Prostate Malignancy

It is demonstrated that altered zinc accumulation is an important factor in this transformation of zinc-accumulating citrate-producing normal prostate epithelial cells tocitrate-oxidizing malignant cells in the process of malignancy.

The Pyruvate Dehydrogenase E1 Alpha Gene Is Testosterone And Prolactin Regulated In Prostate Epithelial Cells

To the authors' knowledge this represents the first report in any mammalian cells that, in addition to its constitutive expression in all mammalian cells, the E1a gene is a hormonally-regulated gene in specifically targeted prostate epithelial cells.

Zinc and zinc transporters in prostate carcinogenesis

The healthy human prostate accumulates the highest level of zinc of any soft tissue in the body. This unique property is retained in BPH, but is lost in prostatic malignancy, which implicates changes

Evidence for a Zinc Uptake Transporter in Human Prostate Cancer Cells Which Is Regulated by Prolactin and Testosterone*

The studies support the concept that these prostate cells express a unique hormone-responsive, plasma membrane-associated, rapid zinc uptake transporter gene associated with their unique ability to accumulate high zinc levels.

Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues

The results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells; so that deficient m-ACP enzyme is not associated with the limiting m-aconsitase activity that prevents citrate oxidation in these cells.

Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats

The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid, links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression.



Concepts of citrate production and secretion by prostate 1. Metabolic relationships

It is hoped that this review will bring attention to the importance and urgency of elucidating and understanding the metabolic relationships associated with citrate production by normal and neoplastic prostate epithelial cells.

Prolactin and testosterone regulation of mitochondrial zinc in prostate epithelial cells

The results demonstrate that the mitochondrial zinc levels of the prostate cells were higher than levels of nonprostatic cells and support the concept that mitochondrial zinc is an inhibitor of m‐aconitase and citrate oxidation in citrate‐producing prostate epithelial cells.

Zinc Inhibition of Mitochondrial Aconitase and Its Importance in Citrate Metabolism of Prostate Epithelial Cells*

In prostate epithelial cells, in situ mitochondrial zinc levels inhibit m-aconitase activity, which provides a mechanism by which citrate oxidation is limited, and is revealed for the first time that zinc is a specific inhibitor of m-aconsitase of mammalian cells.

The effect of testosterone on citrate synthesis and citrate oxidation and a proposed mechanism for regulation of net citrate production in prostate.

These studies support the proposal that aspartate is a major source of oxalacetate for citrate production, and that a "glutamate-aspartate-citrate" pathway may be functional in prostate mitochondria, and can regulate citrates production by a specific effect on mitochondrial aspartates aminotransferase activity.

Concepts of citrate production and secretion by prostate: 2. Hormonal relationships in normal and neoplastic prostate

Concepts of the pathogenesis of prostatic neoplasms are presented based on hormonal, metabolic, and homologous relationships associated with citrate production and the urgency and necessity for research relating to all aspects of prostatecitrate production in normal and pathological prostate are emphasized.

Citrate modulation of high-affinity aspartate transport in prostate epithelial cells.

The concept that citrate is a physiological regulator of the high-affinity transport of aspartate into prostate secretory epithelial cells in association with the unique and highly specialized function of net citrate production and secretion is supported.

Bioenergetic theory of prostate malignancy

It is proposed that the process of malignancy necessitates an energy production that cannot be provided by citrate‐producing cells, and the transformation of prostate epithelial cells to citrate-oxidizing cells which increases the energy production capability is essential to theprocess ofmalignancy and metastasis.