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Zinc, DHEA, Cholesterol, and Folate

Zinc

May 2015

By Life Extension

Zinc transporters in prostate cancer.

Prostate cancer is a major health concern as it has the second highest incidence rate among cancers in men. Despite progress in tumor diagnostics and therapeutic approaches, prognosis for men with advanced disease remains poor. In this review we provide insight into the changes of the intermediary metabolism in normal prostate and prostate cancer. In contrast to normal cells, prostate cancer cells are reprogrammed for optimal energy-efficiency with a functional Krebs cycle and minimal apoptosis rates. A key element in this relationship is the uniquely high zinc level of normal prostate epithelial cells. Zinc is transported by the SLC30 and SLC39 families of zinc transporters. However, in prostate cancer the intracellular zinc content is remarkably reduced and expression levels of certain zinc transporters are altered. Here, we summarize the role of different zinc transporters in the development of prostate cancer.

Mol Aspects Med. 2013 Apr-Jun;34(2-3):735-41

Zinc and its transporters, pancreatic- cells, and insulin metabolism.

Zinc is an essential trace metal for life. Two families of zinc transporters, SLC30A (ZNT) and SLC39A (ZIP) are required for maintaining cellular zinc homeostasis. ZNTs function to decrease cytoplasmic zinc concentrations whereas ZIPs do the opposite. Expression of zinc transporters can be tissue/cell-type specific or ubiquitous. Zinc transporters that are limited in tissue/cell distributions usually perform specialized tasks to satisfy biological processes in a given cell. For example, ZNT8 is mainly expressed in b-cells and functions to deliver zinc into granules for insulin maturation and secretion. Many other zinc transporters are also expressed in b-cells. Defects in these zinc transporters have been associated with abnormalities in insulin synthesis, maturation, and secretion and subsequent glucose metabolism. This review focuses on the specific roles of zinc and its transporters in insulin metabolism and describes the current knowledge of the function of zinc transporters in b-cell health in animal knockout mouse models with respect to diabetes development in humans.

Vitam Horm. 2014;95:365-90

Zinc and zinc transporters in normal prostate and the pathogenesis of prostate cancer.

Zinc is an essential metal for all cells. It plays a role in a wide variety of physiological and biochemical processes. In the prostate epithelial cell the accumulation of high cellular zinc is a specialized function that is necessary for these cells to carry out the major physiological functions of production and secretion of citrate. The production of citrate and its secretion into prostatic fluid is a differentiated function of the prostate epithelial cells that is apparently important for reproduction. The loss of citrate and zinc accumulation is the most consistent and persistent characteristic of prostate malignancy. This characteristic of prostate cancer indicates that the lost ability of the malignant cells to accumulate zinc and citrate is an important factor in the development and progression of malignancy. The lost ability of the epithelial cells to accumulate zinc and thus to also accumulate citrate is the result of decreased expression of specific zinc uptake transporters. The purpose of this presentation is to review the current understanding of zinc and zinc homeostasis in the prostate and the role of zinc and zinc transporters in the normal function of the prostate and the pathogenesis of prostate cancer.

Front Biosci. 2005 Sep 1;10:2230-9

Zinc in the human prostate gland: normal, hyperplastic and cancerous.

Zinc concentration in a prostate gland is much higher than in other human tissues. Data for zinc changes in different prostate diseases are limited and greatly contradictory. To analyze transrectal puncture tissue biopsy and resected materials, zinc content was estimated in benign prostatic hyperplasia (BPH) and cancer. There were 109 patients studied (50 BPH and 59 cancer). The control group consisted of 37 intact glands of men who died an unexpected death (accident, murder, acute cardiac insufficiency, etc.). All materials studied were divided into two parts. One of them was morphologically examined, while the zinc content of another one was estimated. The radionuclide induced energy dispersive X-ray fluorescent analysis was used for zinc determination. Zinc content (M +/- SE) of normal prostate, BPH and cancer was 1018 +/- 124, 1142 +/- 77, and 146 +/- 10 micrograms/g dry tissue, respectively. It was shown that zinc assessment in the material of transrectal puncture biopsy of prostate indurated site can be used as an additional test for differential diagnosis of BPH and cancer. Accuracy, sensitivity and specificity of the test are 98 +/- 2%.

Int Urol Nephrol. 1997;29(5):565-74

A Critical Assessment of Epidemiology Studies Regarding Dietary/Supplemental Zinc and Prostate Cancer Risk.

Despite the prevalence of prostate cancer, the etiology and factors associated with its development and progression are largely unknown. An important relationship in prostate cancer is the role of zinc. Clinical evidence and experimental evidence have established that prostate cancer is associated with a decrease in the zinc uptake and accumulation in the malignant cells; and that the accumulation of zinc in the prostate cells prevents malignancy. In contrast to this established consistent clinical relationship, numerous epidemiology studies and reports of the effect of dietary and supplemental zinc on the incidence of prostate cancer have provided divergent, inconsistent, and inconclusive results; which range from adverse effects of zinc, protective effects of zinc, and no effect of zinc on the risk of prostate cancer. Despite these divergent and inconclusive results, a prevailing view and public warning has evolved from unsubstantiated and uncorroborated epidemiology studies that zinc consumption increases the risk of developing advanced stage prostate cancer. Such a conclusion is not well-founded and has serious, confusing and erroneous implications for the medical/scientific community and for the public-at-large. The admonition of Dimitrios Trichopoulos over a decade ago [1] that, “ … (epidemiology) studies will inevitably generate false positive and false negative results with disturbing frequency. …, when (people) do take us seriously, we may unintentionally do more harm than good ” can be applied to the situation that is the subject of this report. Therefore it is extremely important to review the epidemiology studies that have lead to the conclusion of an adverse effect of zinc, and also that have produced such inconsistent and divergent results. This critical review defines issues, problems, and shortcomings that exist in the conduct, conclusions, and dissemination of the epidemiology studies. We caution that one should be knowledgeable and understanding of these issues in assessing the validity and the conclusiveness of the outcomes from the epidemiology studies of purported associations of dietary and supplemental zinc on the risk of prostate cancer; particularly when the unsubstantiated conclusions are at odds with clinical and experimental evidence. It is in the interest of the medical, scientific and public communities that this critical review is undertaken. We hope that this review will generate an open, objective, scientific and medical discussion and assessment of this important issue.

Open Urol Nephrol J. 2008;1

Zinc as an anti-tumor agent in prostate cancer and in other cancers.

Human prostate glandular epithelial cells have the unique capability of accumulating high levels of zinc. This is essential to inhibit m-aconitase activity so that citrate can accumulate for secretion into prostatic fluid, which is a major function of the prostate gland. As a result, the Krebs cycle is truncated with the consequence of the lost ATP production that would result from citrate oxidation. The cellular accumulation of zinc also inhibits mitochondrial terminal oxidation and respiration. In addition to these metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. Zinc accumulation also inhibits the invasive/migration activities in malignant prostate cells. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc. The ability of prostate cells to accumulate zinc is due to the expression and activity of the zinc uptake transporter, ZIP1. To avoid the anti-tumor effects of zinc, in prostate cancer the malignant prostate cells exhibit a silencing of ZIP1 gene expression accompanied by a depletion of cellular zinc. Therefore we regard ZIP1 as a tumor suppressor gene in prostate cancer. In addition to prostate cells, similar tumor suppressor effects of zinc have been identified in several other types of tumors.

Arch Biochem Biophys. 2007 Jul 15;463(2):211-7

Serum zinc and prostate cancer risk in a nested case-control study: The multiethnic cohort.

BACKGROUND: Experimental studies have provided evidence that zinc has a protective effect against development and progression of prostate cancer. However, epidemiological studies have reported inconsistent findings. We evaluated the association between prediagnostic serum zinc and prostate cancer risk in a cohort of multiethnic population. METHODS: This case-control study is nested within the Multiethnic Cohort of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in Hawaii and California. The analysis included 392 prostate cancer cases and 783 controls matched on age, race/ethnicity, date/time of blood draw and fasting status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The mean serum zinc concentrations did not significantly differ between cases (94.9 µg/dl) and controls (93.9 µg/dl). No association was found between serum zinc levels and prostate cancer either overall or by tumor stage/grade. In ethnic-specific analyses, positive associations were found in Japanese Americans (OR for the highest vs. the lowest tertile = 2.59, 95% CI: 1.09-6.17) and Latinos (OR = 2.74, 95% CI: 1.05-7.10), whereas no association was observed in African Americans and whites. CONCLUSIONS: We found no evidence to support an inverse relationship between serum zinc and prostate cancer risk, and, to the contrary, found a suggestion in the ethnic-specific results of a possible increase in risk; however, blood concentrations of zinc may not adequately reflect the levels in prostate tissue. Further study with a larger sample size, and if possible, with assessment of zinc tissue levels, is warranted to confirm these findings

Prostate. 2013 Feb 15;73(3):261-6

Dietary zinc and prostate cancer in the TRAMP mouse model.

Circumstantial evidence indicates that zinc may have an important role in the prostate. Total zinc levels in the prostate are 10 times higher than in other soft tissues. Zinc concentrations in prostate epithethial cancer cells are decreased significantly. Zinc supplementation for prevention and treatment of prostate cancer in humans has yielded controversial results. No studies have been reported in animal models to show the effect of zinc supplementation on prevention of prostate cancer, thus far. In this study, we have examined the effect of zinc supplementation on development of prostate cancer in a TRAMP mouse model. Results from our study indicate that dietary zinc plays an important role in prostate carcinogenesis. Tumor weights were significantly higher when the dietary zinc intake was either deficient or high in comparison to normal zinc intake level, suggesting that an optimal dietary zinc intake may play a protective role against prostate cancer. Further, our studies also showed decreased insulin-like growth factor (IGF)-1 and IGF-1/IGF binding protein-3 ratio in normal zinc-supplemented animals, suggesting that zinc may modulate IGF-1 metabolism in relation to carcinogenesis. We conclude that optimal prostate zinc concentration has a protective role against cancer.

J Med Food. 2010 Feb;13(1):70-6

The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots.

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 prostate 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. RESULTS: The specialized function of the normal prostate glandular epithelium to produce and secrete enormously high levels of citrate involves and requires unique intermediary metabolism activities that are not generally associated with other normal mammalian cells. The accumulation of zinc by these cells is an essential factor in this unique metabolic relationship. In malignancy, the normal zinc-accumulating citrate-producing epithelial cells are metabolically transformed to citrate-oxidizing cells that lose the ability to accumulate zinc. A genetic alteration in the expression of ZIP1 zinc transporter is associated with this metabolic transformation. These genetic/metabolic relationships have important consequences on citrate-related metabolism, bioenergetics, cell proliferation and invasive capabilities of the malignant cells, which result in tumor-suppression characteristics. CONCLUSION: The genetic/metabolic relationships in normal prostate glandular epithelium are driven by the unique function to accumulate and secrete citrate. The genetic/metabolic transformation of the prostate malignant cells is driven by the metabolic/bioenergetic, growth/proliferative, and invasive/migration requirements of the malignant process. Zinc is critical to these relationships. An understanding of these genetic/metabolic relationships provides new directions and opportunities for development of regimens for the prevention and treatment of prostate cancer. Important insight into the genetic/metabolic requirements of the prostate malignant process is now evolving. Most importantly at this time, an appreciation and recognition of the genetic/metabolic significance and implications in the development of prostate malignancy is imperative; and much needed research in this area is essential. Hopefully, this review will help to achieve these goals.

Mol Cancer. 2006 May 15;5:17

Semenogelin, the predominant protein in human semen. Primary structure and identification of closely related proteins in the male accessory sex glands and on the spermatozoa.

The predominant protein in human semen, semenogelin, was characterized by lambda gt11 clones isolated from a seminal vesicular cDNA library. One clone, carrying a cDNA insert of 1606 nucleotides and a polyadenylated tail, coded for the entire semenogelin precursor. An open reading frame of 1386 nucleotides encodes a signal peptide and the mature protein of 439 amino acid residues, in which residues 85-136 are identical with a previously characterized semenogelin fragment. The polypeptide chain displays a most conspicuous region of internal sequence homology where 46 of the 58 amino acid residues at positions 259-316 are repeated at positions 319-376. An abundant seminal vesicular transcript of 1.8 kilobases (kb) codes for semenogelin. Two additional transcripts, one seminal vesicular 2.2-kb species and one epididymal 2.0-kb species, code for related proteins that have a close structural relationship as well as antigenic epitopes in common with semenogelin. Semenogelin and the semenogelin-related proteins are the major proteins involved in the gelatinous entrapment of ejaculated spermatozoa. Antigenic epitopes common to these proteins are localized to the parts of the spermatozoa involved in locomotion. The spermatozoa become progressively motile as the gel-forming proteins are fragmented by the kallikrein-like protease, prostate-specific antigen, and the gel dissolves.

J Biol Chem. 1989 Jan 25;264(3):1894-900

The pH of prostatic fluid: a reappraisal and therapeutic implications.

A basic assumption in all experiments on prostatic physiology, particularly those designed to study the diffusion of drugs into the prostate gland, is that the pH of human prostatic fluid is similar to that of the dog, that is pH 6.1 to 6.5. We believe that this assumption is incorrect. Our data indicate 1) the expressed prostatic secretion of most normal men is alkaline (mean pH 7.31), 2) with prostatic infection the pH of prostatic fluid increases markedly (mean pH 8.34) and, therefore, drugs shown to diffuse into the canine prostate may be ineffective in treating prostatitis in humans and 3) the increase in pH of the expressed prostatic secretion seen with infection is not simply owing to an increase in the relative concentration of alkaline seminal vesicular components. Biochemical markers of seminal vesicular activity (fructose and prostaglandins) showed no correlation with pH values of expressed prostatic secretion. Hence, it appears that the change in pH of the expressed secretion is owing to a real increase in pH of prostatic fluid. The clinical implications of these findings are discussed. An appreciation of the profound variation in the prostatic fluid pH may be of importance not only in furthering the understanding and treatment of chronic bacterial prostatitis but, also, of other prostatic diseases as well.

J Urol. 1978 Dec;120(6):695-8

Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity.

A major issue relating to many cancers is the absence of effective chemotherapeutic agents; so that most often untreatable morbidity and death are prevalent once the cancer has been detected and has advanced. The search for efficacious anticancer agents is imperative. One potential agent is zinc, which is decreased in the development of some cancers in order to avoid its cytotoxic/tumor suppressor effects on the malignant cells. This provides the basis and opportunity to employ a treatment regimen that restores elevated zinc levels in the malignant cells and elicits the cytotoxic/tumor suppressor effects of zinc. The enigma is that this approach and expectation has not reached fruition. The question is “why?”. This article provides a discussion of relevant zinc issues that need to be considered and resolved. Important areas of research are identified as being essential for the successful application of zinc cytotoxicity/tumor suppression actions for the treatment of specific cancers.

Expert Rev Anticancer Ther. 2012 Jan;12(1):121-8