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

BackgroundIn prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-aconitase activity in prostate epithelial cells could be the result of a decreased level of m-aconitase enzyme and/or the inhibition of existing m-aconitase. Earlier studies identified zinc as an inhibitor of m-aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines.ResultsThe immunocytochemical procedure successfully identified the presence of m-aconitase localized in the mitochondrial compartment in PC-3, LNCaP, and DU-145 malignant prostate cell lines. The examination of prostate tissue sections from prostate cancer subjects demonstrated that m-aconitase enzyme is present in the glandular epithelium of normal glands, hyperplastic glands, adenocrcinomatous glands, and prostatic intraepithelial neoplastic foci. Quantitative analysis of the relative level of m-aconitase in the glandular epithelium of citrate-producing adenomatous glands versus the citrate-oxidizing adenocarcinomatous glands revealed no significant difference in m-aconitase enzyme levels. This is in contrast to the down-regulation of ZIP1 zinc transporter in the malignant glands versus hyperplastic glands that exists in the same tissue samples.ConclusionThe results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells; so that deficient m-aconitase enzyme is not associated with the limiting m-aconitase activity that prevents citrate oxidation in these cells. The level of m-aconitase is maintained in the malignant cells; so that an altered enzyme level is not associated with the increased m-aconitase activity. Consequently, the elevated zinc level that inhibits m-aconitase enzyme is responsible for the impaired citrate oxidation in normal and hyperplastic prostate glandular epithelial cells. Moreover, the down-regulation of ZIP1 zinc transporter and corresponding depletion of zinc results in the increase in the activity of the existing m-aconitase activity in the malignant prostate cells. The studies now define the mechanism for the metabolic transformation that characterizes the essential transition of normal citrate-producing epithelial cells to malignant citrate-oxidizing cells.

[1]  C. Coopersmith,et al.  Epithelial cells , 1991 .

[2]  R. Franklin,et al.  Testosterone stimulates the biosynthesis of m-aconitase and citrate oxidation in prostate epithelial cells , 1995, Molecular and Cellular Endocrinology.

[3]  Y. Ozaki,et al.  Role of Apoptosis Controlled by Cytochrome c Released from Mitochondria for Luteal Function in Human Granulosa Cells , 2005, American journal of reproductive immunology.

[4]  R. Franklin,et al.  The Intermediary Metabolism of the Prostate: A Key to Understanding the Pathogenesis and Progression of Prostate Malignancy , 2000, Oncology.

[5]  P. Narayan,et al.  Citrate in the diagnosis of prostate cancer , 1999, The Prostate.

[6]  R. Franklin,et al.  Zinc causes a shift toward citrate at equilibrium of the m-aconitase reaction of prostate mitochondria. , 2000, Journal of inorganic biochemistry.

[7]  J. Kurhanewicz,et al.  Combined magnetic resonance imaging and spectroscopic imaging approach to molecular imaging of prostate cancer , 2002, Journal of magnetic resonance imaging : JMRI.

[8]  R. Franklin,et al.  Mitochondrial function, zinc, and intermediary metabolism relationships in normal prostate and prostate cancer. , 2005, Mitochondrion.

[9]  M. Tan,et al.  Role of zinc in the pathogenesis and treatment of prostate cancer: critical issues to resolve , 2004, Prostate Cancer and Prostatic Diseases.

[10]  B. Rowan,et al.  Src Kinase and Mitogen-Activated Protein Kinases in the Progression from Normal to Malignant Endometrium , 2004, Clinical Cancer Research.

[11]  R. Franklin,et al.  Citrate and isocitrate utilization by rat ventral prostate mitochondria. , 1978, Enzyme.

[12]  R. Franklin,et al.  Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. , 2002, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[13]  R. Franklin,et al.  Testosterone and prolactin stimulation of mitochondrial aconitase in pig prostate epithelial cells. , 1996, Urology.

[14]  Franklin Rb,et al.  Citrate uptake and oxidation by fragments of rat ventral prostate. , 1977 .

[15]  R. Franklin,et al.  Mitochondrial isocitrate dehydrogenase and isocitrate oxidation of rat ventral prostate. , 1976, Enzyme.

[16]  R. Franklin,et al.  Mitochondrial aconitase gene expression is regulated by testosterone and prolactin in prostate epithelial cells , 2000, The Prostate.

[17]  R. Franklin,et al.  Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer , 1998, The Prostate.

[18]  R. Franklin,et al.  Zinc Inhibition of Mitochondrial Aconitase and Its Importance in Citrate Metabolism of Prostate Epithelial Cells* , 1997, The Journal of Biological Chemistry.

[19]  R. Franklin,et al.  Concepts of citrate production and secretion by prostate 1. Metabolic relationships , 1991, The Prostate.

[20]  H. Juang.  Modulation of mitochondrial aconitase on the bioenergy of human prostate carcinoma cells. , 2004, Molecular genetics and metabolism.