NOVEL ROLE OF ZINC IN THE REGULATION OF PROSTATE CITRATE METABOLISM AND ITS IMPLICATIONS IN PROSTATE-CANCER

The prostate gland of humans and many other animals has the major func tion of accumulating and secreting extraordinarily high levels of citr ate. This specialized metabolic process of ''net citrate production'' is the result of unique metabolic capabilities of the secretory epithe lial 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 levels of zinc in the body. As with citrate, in Pea the abilit y for high zinc accumulation is diminished. These and other correlatio ns between zinc and citrate in the prostate have been indicative of an important role of zinc in the regulation of citrate metabolism in nor mal and malignant prostate epithelial cells. The link between zinc and citrate metabolism has now been established. The intramitochondrial a ccumulation of high zinc levels inhibits mitochondrial (m-) aconitase activity, which inhibits citrate oxidation. This essentially truncates the Krebs cycle and markedly decreases the cellular energy (ATP) prod uction normally coupled to citrate oxidation. It is also clear that zi nc accumulation in citrate-producing prostate epithelial cells is regu lated by testosterone and by prolactin. These relationships form the b asis for a new concept of the role of zinc and citrate-related energy metabolism in prostate malignancy. The inability of malignant prostate cells to accumulate high zinc levels results in increased citrate oxi dation and the coupled ATP production essential for the progression of malignancy. The concept offers new approaches to the treatment of Pea . (C) 1998 Wiley-Liss, Inc.