This review emphasizes the importance and role of altered intermediary metabolism of prostate cells in the pathogenesis of prostate adenocarcinoma (PCa) and the progression of malignancy. The focus of the presentation is a summary of the overwhelming evidence which implicates the metabolic transformation of citrate-producing sane cells to citrate-oxidizing malignant cells in the process of malignancy. The evidence now demonstrates that altered zinc accumulation is an important factor in this transformation. These metabolic relationships are uniquely different from the metabolic alterations associated with tumorigenesis of other mammalian cells. The metabolic transformation of zinc-accumulating citrate-producing normal prostate epithelial cells to citrate-oxidizing malignant cells has important implications on cellular bioenergetics, cell growth and apoptosis, lipogenesis, angiogenesis. Based on the metabolic considerations new concepts concerning the pathogenesis, diagnosis and treatment of prostate malignancy are presented. Unfortunately the metabolism of the prostate has been a seriously neglected and largely ignored area of prostate research. The importance of expanded research into the intermediary metabolism of normal and neoplastic prostate is essential to future significant advances in understanding and dealing with PCa.

1.
Costello LC, Franklin RB: Citrate metabolism of normal and malignant prostate epithelial cells. Urology 1997;50:3–12.
2.
Costello LC, Franklin RB: Intermediary energy metabolism of normal and malignant prostate epithelial cells; in Naz RK (ed): Prostate: Basic and Clinical Aspects. New York, CRC Press, 1997, pp 115–150.
3.
Costello LC, Franklin RB: The novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. Prostate 1998;35:285–296.
4.
Costello LC, Franklin RB, Narayan P; Citrate in the diagnosis of prostate cancer. Prostate 1999;38:237–245.
5.
Huggins C: The prostate secretion. Harvey Lect 1946;52:148–193.
6.
Harkonen PL: Androgenic control of glycolysis, the pentose cycle and pyruvate dehydrogenase in the rat ventral prostate. J Steroid Biochem Mol Biol 1981;14:1075–1084.
7.
Kavanagh JP: Sodium, potassium, calcium, magnesium, zinc, citrate and chloride content of human prostatic and seminal fluid. J Reprod 1985;75:35–41.
8.
Mann T, Lutwak-Mann C: Male Reproductive Function and Semen. Berlin, Springer, 1981.
9.
Hicks JJ; Martinez-Manautou J, Pedron N, Rosado A: Metabolic changes in human spermatozoa related to capacitation. Fertil Steril 1972;23:172–179.
10.
Arver S: Zinc and zinc ligands in human seminal plasma. Acta Physiol Scand 1982;116:67–73.
11.
Tomlins AM, Foxall PJ, Lynch MJ, Parkinson J, Everett JR, Nicholson JK: High resolution 1H NMR spectroscopic studies on dynamic biochemical processes in incubated human seminal fluid samples. Biochim Biophys Acta 1998;1379:367–380.
12.
Barron ESG, Huggins C: The metabolism of isolated prostatic tissue. J Urol 1944;51:630–634.
13.
Muntzing J, Varkarakis MJ, Saroff J, Murphy GP: Comparison and significance of respiration and glycolysis of prostatic tissue from various species. J Med Primatol 1975;4:245–251.
14.
Farnsworth WE: Testosterone stimulation of citric acid synthesis in the rat prostate. Biochim Biophys Acta 1966;117:247–254.
15.
Harkonen P, Isotala A, Santti R: Studies on the mechanism of testosterone action on glucose metabolism in rat ventral prostate. J Steroid Biochem 1975;6:1405–1413.
16.
Santti RS, Villee CA: Hormonal control of hexokinase in male sex accessory glands. Endocrinology 1971;89:1162–1170.
17.
Costello LC, Akuffo V, Franklin RB: Net citrate production by isolated prostate epithelial cells. Enzyme 1988;39:125–133.
18.
Feichter A, Gmunder FK: Metabolic control of glucose degradation in yeast and tumor cells. Adv Biochem Eng Biotechnol 1989;39:1–28.
19.
Cai G-Z, Callaci TP, Luther MA, Lee JC: Regulation of rabbit muscle phosphofructokinase by phosphorylation. Biophys Chem 1997;64:199–209.
20.
Feichter A, Gmunder FK: Metabolic control of glucose degradation in yeast and tumor cells. Adv Biochem Eng Biotechnol 1989;39:1–28.
21.
Ramaiah A: Pasteur effect and phosphofructokinase. Curr Topics Cell Regul 1974;8:297–345.
22.
Li Y, Rivera D, Ru W, Gunasekers D, Kemo RG: Identification of allosteric sites in rabbit phosphofructo-1-kinase. Biochemistry 1999;38:16407–16412.
23.
Cooper JE, Farid I: The role of citric acid in the physiology of the prostate: Lactic/citrate ratios in benign and malignant prostatic homogenates as an index of prostatic malignancy. J Urol 1964;92:533–536.
24.
Cooper JF, Imfeld H: The role of citric acid in the physiology of the prostate: A preliminary report. J Urol 1959;81:157–163.
25.
Marberger H, Marberger E, Mann T, Lutwak-Mann C: Citric acid in human prostatic secretion and metastasizing cancer of prostate gland. BMJ 1962;i:835–836.
26.
Costello LC, Littleton GK, Franklin RB: Regulation of citrate-related metabolism in normal and neoplastic prostate; in Sharam RK, Criss WE (eds): Endocrine Control in Neoplasia. New York, Raven Press, 1978, pp 303–314.
27.
Kurhanewicz J, Vigneron DB, Males RG, Swanson MG, Yu KY, Hricak H: The prostate: Imaging and spectroscopy. Radiol Clin North Am 2000;38:115–138.
28.
Costello LC, Franklin RB: Concepts of citrate production and secretion by prostate. 2. Hormonal relationships in normal and neoplastic prostate. Prostate 1991;19:191–205.
29.
Warburg O, Wind F, Negelein E: Über den Stoffwechsel von Tumoren im Körper. Klin Wochenschr 1926;5:829–832.
30.
Parlo RA, Coleman PS: Enhanced rate of citrate export from cholesterol-rich hepatoma mitochondria. J Biol Chem 1984;259:9997–10003.
31.
Baggetto LG: Deviant energetic metabolism of glycolytic cancer cells. Biochimie 1992;74:959–974.
32.
Argiles JM, Lopez-Soriano FJ: Why do cancer cells have such a high glycolytic rate. Med Hypotheses 1990;32:151–155.
33.
Costello LC, Franklin RB: Bioenergetic theory of prostate malignancy. Prostate 1994;25:162–166.
34.
Dang CV, Semenza GL: Oncogenic alterations of metabolism. Trends Biochem Sci 1999;24:68–72.
35.
Movsas B, Chapman JD, Horwitz EM, Pinover WH, Greenberg RE, Hanlon AL, Iyer R, Hanks GE: Hypoxic regions exist in human prostate carcinoma. Urology 1999;53:11–18.
36.
Zhong H, Agani F, Baccala AA, Laughner E, Rioseco-Camacho N, Isaacs WB, Simons JW, Semenza GL: Increased expression of hypoxia inducible factor-1 alpha in rat and human prostate cancer. Cancer Res 1998;58:5280–5284.
37.
Zhong H, De Marzo AM, Laughner E, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Over-expression of hypoxia-inducible factor 1 alpha in common human cancers and their metastases. Cancer Res 1999;59:5830–5835.
38.
Swinnen J, Ulrix W, Heyns W, Verhoeven G: Coordinate regulation of lipogenic gene expression by androgens: Evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc Natl Acad Sci USA 1997;94:12975–12980.
39.
Swinnen J, Verhoeven G: Androgens and the control of lipid metabolism in human prostate cancer cells. J Steroid Biochem Mol Biol 1998;65:191–198.
40.
Arunakaran J, Balasubramanian K, Srinivasan N, Aruldhas MM, Govindarajulu P: Interaction of androgens and prolactin on prostatic enzymes of the pyruvate-malate cycle involved in lipogenesis in castrated mature monkey, Macaca radiata. Cytobios 1992;70:33–40.
41.
Halliday KR, Fenoglio-Preiser C, Sillerud LO: Differentiation of human tumors from nonmalignant tissue by natural-abundance 13C NMR spectroscopy. Magn Reson Med 1988;7:384–411.
42.
Kurhanewicz J, Vigneron DB, Hricak H, Narayan P, Carroll P, Nelson SJ: Three dimensional hydrogen-1 MR spectroscopic imaging of the situ human prostate with high spatial resolution. Radiology 1996;198:795–805.
43.
Zaichick VY, Sviridova TV, Zaichick SV: Zinc in the human prostate gland: Normal hyperplasia, cancerous. Int Urol Nephrol 1997;29:565–574.
44.
Liney GP, Turnbull LW, Lowry M, Turnbull LS, Knowles AJ, Horsman A: In vivo quantification of citrate concentration and water T2 relaxation time of the pathologic prostate gland using 1H MRS and MRI. Magn Reson Imaging 1997;15:1177–1186.
45.
Liu Y, Costello LC, Franklin RB: Prolactin and testosterone regulation of mitochondrial zinc in prostate epithelial cells. Prostate 1997;30:26–32.
46.
Costello LC, Liu Y, Franklin RB, Kennedy MC: Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells. J Biol Chem 1997;272:28875–28881.
47.
Costello LC, Franklin RB, Liu Y, Kennedy MC: Zinc causes a shift toward citrate at equilibrium of the m-aconitase reaction of prostate mitochondria. Inorg Biochem 2000:78:161–165.
48.
Liang J-Y, Liu Y, Zou J, Franklin RB, Costello LC, Feng P: Inhibitory effect of zinc on human prostatic cell growth. Prostate 1999;40:200–207.
49.
Feng P, Liang J-Y, Li T-L, Guan Z-X, Zou J, Franklin RB, Costello LC: Zinc induces mitochondrial apoptogenesis in prostate cells. Mol Urol 2000;4:31–35.
50.
Perlman H, Zhang X, Chen MW, Walsh K, Buttyan R: An elevated bax/bcl-2 ratio corresponds with the onset of prostate epithelial cell apoptosis. Cell Death Differ 1999;6:48–54.
51.
Furuya Y, Krajewski S, Epstein JI, Reed JC, Isaacs JT: Expression of bcl-2 and the progression of human and rodent prostatic cancers. Clin Cancer Res 1996;2:389–398.
52.
Colembel M, Symmans F, Gils S, O’Toole KM, Chopin D, Benson M, Olsson CA, Korsmeyer S, Buttyan R: Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone-refactory human prostate cancers. Am J Pathol 1993;143:390–400.
53.
Costello LC, Liu Y, Zou J, Franklin RB: Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone. J Biol Chem 1999;274:17499–17504.
54.
Habib FK, Mason MK, Smith PH, Stitch SR: Cancer of the prostate: Early diagnosis by zinc and hormone analysis. Br J Cancer 1979;39:700–704.
55.
Heerschap A, Jager GJ, van der Graaf M, Barentsz JO, De La Rossette JJMCH, Oosterhof GON, Ruijter ETG, Ruijs SHJ: In vivo proton MR spectroscopy reveals altered metabolite content in malignant prostate tissue. Anticancer Res 1997;17:1455–1460.
56.
Pickett B, Vigneault E, Kurhanewicz J, Verhey L, Roach M: Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 1999;43:921–929.
57.
Zaichick VY, Sviridova TV, Zaichick SV: Zinc concentration in human prostatic fluid: Normal, chronic prostatitis, adenoma and cancer. Int Urol Nephrol 1996;28:687–694.
58.
Anderson RU, Fair WR: Physical and chemical determinations of prostatic secretion in benign hyperplasia, prostatitis and adenocarcinoma. Invest Urol 1976;14:137–140.
59.
Kavanagh JP, Darby C, Costello CB: The response of seven prostatic fluid components to prostatic disease. Int J Androl 1982;5:487–496.
60.
Fair WR, Cordonnier JJ: The pH of prostatic fluid: A reappraisal and therapeutic implications. J Urol 1978;120:695–698.
61.
Costello LC, Liu Y, Zou J, Franklin RB: Mitochondrial aconitase gene expression is regulated by testosterone and prolactin in prostate epithelial cells. Prostate 2000;42:196–202.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.