Diletta Garrou, Alice Montanaro
Introduction
The incidence of prostate cancer has been increasing worldwide, with the greatest increases in the US. It is the most common cancer other than skin cancer among US men. The etiology of prostate cancer is poorly understood; age, family history, and race are among the few established risk factors. The human prostate gland is a complex organ comprised of different zones that have different embryological origin and different functional activities. The focus is the peripheral zone (70% of the gland) that is the major functional component. Most importantly, this is the major region of malignancy.
The primary function of the prostate gland is the production and secretion of prostatic fluid that contain high concentration of citrate, which ranges from ~40–150 mM as contrasted with ~0.2 mM citrate in blood plasma. The function of prostate citrate production is achieved by the activity of highly specialized glandular epithelial cells that have evolved for the capability to accumulate and secrete citrate, which we refer to as net citrate production (Zinc intake from supplements and diet and prostate cancer. 2009)
There are several lines of evidence that suggest that zinc may play an important and direct role in the prostate. Studies have found that total zinc levels in the prostate are 10 times higher than in other soft tissues. Furthermore, adenocarcinoma cells taken from prostate tumors have lost their ability to amass zinc, whereas in normal prostate cells, zinc is highly concentrated intracellularly in glandular epithelium and inhibits mitochondria aconitase resulting in decreased citrate oxidase . The prevention of citrate oxidation by the prostate cells is the key relationship that is responsible for net citrate production. This metabolic effect has implications in altering energy metabolism and adenosine triphosphate production of prostate cells, such that lower zinc levels in prostate cells leads to a higher rate of citrate oxidation, which increases the available energy and has been proposed to contribute to carcinogenesis and tumor growth.
In contrast to these highly specialized prostate cells, most mammalian cells cannot survive if m-aconitase activity and citrate oxidation are inhibited as is evident from the toxic effects of the m-aconitase inhibitor, fluorocitrate.
It is now well established that citrate and zinc levels are markedly decreased in malignant versus normal prostate tissue. These biochemical changes occur early in the development of malignancy. Moreover, malignant prostate tissue virtually never retains the characteristic high levels of citrate and zinc found in normal peripheral zone. In the absence of high cellular zinc levels, m-aconitase activity is no longer inhibited and citrate oxidation proceeds via the Krebs cycle. Thus we characterize the metabolic transformation as the transformation of zinc-accumulating citrate-oxidizing normal prostate epithelial cells to citrate-oxidizing cells that have lost the ability to accumulate zinc.
An important benefit of this metabolic transformation is the bioenergetic relationship in that citrate oxidation provides the additional 24ATP from complete glucose oxidation that were lost by incomplete glucose oxidation in net citrate production. Thus, the malignant cells are bioenergetically more efficient than the specialized normal prostate epithelial cells. This is in contrast to the general tumor metabolism relationship in which the tumor cells are metabolically transformed to high aerobic glycolysis.
In July of 2003 there was published an article on Journal of the National Cancer Institute that examined the association between supplemental zinc intake and prostate cancer risk in 46976 US men during 14 years of follow-up from 1986 through 2000. Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, compared with nonusers, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer of 2.29 and men who took supplemental zinc for 10 or more years had a relative risk of 2.37.
However, results of other studies suggest that high intraprostatic zinc concentrations may adversely affect prostate cancer risk. For example, zinc enhances the activity of telomerase, an enzyme thought to be responsible for unlimited proliferation of tumor cells and whose activity is increased in prostate cancer.
Whether dietary zinc intake affects intraprostatic zinc levels is unknown.
However, ingestion of 150 mg/day or more of zinc has undesirable metabolic effects, such as immune dysfunction and impaired antioxidant defense , that are potentially related to prostate cancer. (Zinc supplement use and risk of prostate cancer. 2003)
The zinc such as anti-tumoral element is also described by 3 following point:
- As already described, zinc accumulation in prostate cells truncates the Krebs cycle and inhibits citrate oxidation. In addition, high zinc levels also inhibit the respiration and terminal oxidation of prostate mitochondria . These metabolic effects of zinc have bioenergetic and synthetic consequences as already discussed.
- Growth/proliferation effects. The accumulation of zinc inhibits growth and proliferation of prostate cells. We reported that zinc induces apoptogenesis in prostate cells that results from its direct effect on mitochondrial release of cytochrome c followed by activation of the caspase cascade and ultimately apoptosis. This effect is corroborated by the recent report of Huang et al. Uzzo et al reported that zinc sensitized malignant prostate cells to apoptosis through its inhibition of NF-kB. Voce bib ????
- Invasive/migration effects. Zinc has also been shown to inhibit the invasive capabilities of malignant prostate cells.These effects of zinc accumulation are inhibitory to and incompatible with the prostate malignant process and can be defined as "tumor suppressor" effects of zinc.
The depletion of zinc that occurs in malignant prostate cells in situ eliminates these anti-tumor effects. Under these conditions the neoplastic cell is able to meet the metabolic/bioenergetic requirements of malignancy, is able to grow and proliferate, and is able to invade the host tissue and metastasize.
The critical role of Zip1
The critical issue becomes the mechanism involved in the unique ability of normal prostate cells to accumulate high zinc levels; and the mechanism involved in the lost ability of malignant cells to accumulate zinc. The intracellular level of all cells is firstly dependent upon the existence of zinc uptake transporters to extract zinc from external (e.g. interstitial fluid) sources. Many studies have identified hZIP1 as the zinc uptake transporter associated with this transport process.
The first clue was derived from the report of Rishii et al Voce bib ???? who found that ZIP1 expression (determined by RT-in situ-PCR) in prostate glandular epithelium was low in African-American males as compared to Caucasian males. They concluded that this genetic racial difference could account for the higher susceptibility of African-Americans to prostate cancer. In a recent study, the in situ expression and levels of ZIP1 and zinc in malignant versus non-malignant prostate glands in tissues from prostate cancer subjects were determined. The results demonstrated the consistent down regulation of ZIP1 gene expression, the decrease in ZIP1 transporter protein, and the depletion of cellular zinc levels in malignant versus nonmalignant glands. Consequently, as long as ZIP1 transport activity exists and results in high zinc accumulation, the tumor suppressor effects of zinc will prevent the malignant activities of the neoplastic cells. Therefore, is possibile describe ZIP1 as a "tumor suppressor gene in prostate cancer. (The clinical revalence of the metabolism of prostate cancer;zinc and tumor suppression:connecting the dots. 2006)
Zinc absorption
It is well estabilished that
- zinc absorption is reduced when zinc status is high.
- zinc absorption is inhibited by phytic acid found in vegetables and grains.
There is an inverse association between supplemental zinc and prostate cancer in those men
with high consumption of vegetables, suggesting that supplemental zinc may be beneficial
among those who absorb less zinc due to the phytate content of the diet.
There is a significant reduced risk among men who have high vegetable intake (with possible low zinc absorption) and in late-stage prostate cancer.
Thus, our results provide support for the meaningful biological mechanisms that suggest
an important role of zinc in the prostate. If future studies support these results, it may suggest that zinc supplements may be beneficial for some subgroups of men or for the most adverse forms of the disease. (Zinc intake from supplements and diet and prostate cancer. 2009)
It really exists the right amount of Zinc in diet, blood, cells?
Expression of the zinc transporters genes and metallothionein in obese women. 2010
The study determined the expression of zinc transporter protein codifying genes ( ZnT-1, Zip-1 and Zip-3 ) and of metallothionein in 55 obese women, aged between 20 and 56 years.
MRSI imaging in cancer prostate
Editorial Comment on: Combined Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Imaging in the Diagnosis of Prostate Cancer: A Systematic Review and Meta-analysis 2008
Comparison of qualitative and quantitative approach to prostate MR spectroscopyin peripheral zone cancer detection 2010
