Horm Metab Res 2002; 34(8): 417-424
DOI: 10.1055/s-2002-33598
Reviews

© Georg Thieme Verlag Stuttgart · New York

Testosterone and Prolactin Regulation of Metabolic Genes and Citrate Metabolism of Prostate Epithelial Cells

L.  C.  Costello 1 , R.  B.  Franklin 1
  • 1Molecular and Cellular Biology Section, OCBS/Dental School, University of Maryland, Maryland, USA
Further Information

Publication History

Received: 14 February 2002

Accepted after revision: 16 April 2002

Publication Date:
25 September 2002 (online)

Abstract

The control and alteration of key regulatory enzymes is a determinant of the reactions and pathways of intermediary metabolism in mammalian cells. An important mechanism in the metabolic control is the hormonal regulation of the genes associated with the transcription and the biosynthesis of these key enzymes. The secretory epithelial cells of the prostate gland of humans and other animals posses a unique citrate-related metabolic pathway regulated by testosterone and prolactin. This specialized hormone-regulated metabolic activity is responsible for the major prostate function of the production and secretion of extraordinarily high levels of citrate. The key regulatory enzymes directly associated with citrate production in the prostate cells are mitochondrial aspartate aminotransferase, pyruvate dehydogenase, and mitochondrial aconitase. Testosterone and prolactin are involved in the regulation of the corresponding genes associated with these enzymes (which we refer to as “metabolic genes”). The regulatory regions of these genes contain the necessary response elements that confer the ability of both hormones to control gene transcription. In this report, we describe the role of protein kinase c (PKC) as the signaling pathway for the prolactin regulation of the metabolic genes in prostate cells. Testosterone and prolactin regulation of these metabolic genes (which are constitutively expressed in all mammalian cells) is specific for these citrate-producing cells. We hope that this review will provide a strong basis for future studies regarding the hormonal regulation of citrate-related intermediary metabolism. Most importantly, altered citrate metabolism is a persistent distinguishing characteristic (decreased citrate production) of prostate cancer (PCa) and also (increased citrate production) of benign prostatic hyperplasia (BPH). An understanding of the role of hormonal regulation of metabolism is essential to understanding the pathogenesis of prostate disease. The relationships described for the regulation of prostate cell metabolism provides insight into the mechanisms of hormonal regulation of mammalian cells in general.

Rereferences

  • 1 Costello L C, Franklin R B. Citrate metabolism of normal and malignant prostate epithelial cells.  Urol. 1997;  50 3-12
  • 2 Franklin R B, Costello L C. Intermediary energy metabolism of normal and malignant prostate epithelial cells. In: Naz RK (ed) Prostate: Basic and clinical aspects. New York; CRC Press 1997: 115-150
  • 3 Costello L C, Franklin R B. The novel role of zinc in the intermediary metabolism of prostate epitelial cells and its implications in prostate malignancy.  Prostate. 1998;  35 285-296
  • 4 Costello L C, Franklin R B. The intermediary metabolism of the prostate: A key to understanding the pathogenesis and progression of prostate malignancy.  Oncology. 2000;  59 269-282
  • 5 Costello L C, Franklin R B. Concepts of citrate production and secretion by prostate. 2. Hormone relationships in normal and neoplastic prostate.  Prostate. 1991;  19 181-205
  • 6 Costello L C, Franklin R B. Effect of prolactin on the prostate.  Prostate. 1994;  24 162-166
  • 7 Costello L C, Franklin R B. Aconitase activity, citrate oxidation and zinc inhibition in rat ventral prostate.  Enzyme. 1982;  26 281-287
  • 8 Costello L C, Liu Y, Franklin R B, Kennedy M C. Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells.  J Biol Chem. 1997;  272 28 875-28 881
  • 9 Costello L C, Franklin R B, Kennedy M C. Zinc causes a shift toward citrate at equilibrium of the m-aconitase reaction of prostate mitochondria.  J Inorg Biochem. 2000;  78 161-165
  • 10 Humphrey G F, Mann R. Studies on the metabolism of semen. Citric acid in semen.  Biochem J. 1949;  44 97-105
  • 11 Costello L C, Littleton G K, Franklin R B. Citrate and related intermediary metabolism in normal and neoplastic prostate.  In: Endocrine Control in Neoplasia. New York; Raven Press 1978: 304-314
  • 12 Costello L C, Franklin R B. Concepts of citrate production and secretion by prostate. 1. Metabolic relationships.  Prostate. 1991;  18 25-46
  • 13 Franklin R B, Brandly R L, Costello L C. Mitochondrial aspartate, aminotransferase and the effect of testosterone on citrate production in rat ventral prostate.  J Urol. 1982;  127 798-802
  • 14 Franklin R B, Brandly R L, Costello L C. Effect of inhibitors of RNA and protein synthesis on mitochondrial aspartate aminotransferase response to testosterone in rat ventral prostate.  Prostate. 1982;  3 637-642
  • 15 Franklin R B, Kahng M W, Akuffo V, Costello L C. The effect of testosterone on citrate synthesis and citrate oxidation and a proposed mechanism for regulation of net citrate production in prostate.  Horm Metab Res. 1986;  18 177-181
  • 16 Costello L C, Akuffo V, Franklin R B. Testosterone stimulates net citrate production from aspartate by prostate epithelial cells.  Horm Metab Res. 1988;  20 252-253
  • 17 Franklin R B, Qian K, Costello L C. Regulation of aspartate aminotransferase messenger RNA level by testosterone.  J Steroid Biochem. 1990;  35 569-574
  • 18 Qian K, Franklin R B, Costello L C. Testosterone regulates mitochondrial aspartate aminotransferase gene expression and mRNA stability in prostate.  J Steroid Biochem Mol Biol. 1993;  44 13-19
  • 19 Juang H H, Costello L C, Franklin R B. Androgen modulation of multiple transcription start sites of the mAAT gene in rat prostate.  J Biol Chem. 1995;  270 12 629-12 634
  • 20 Harkonen P L. Androgenic control of glycolysis, the pentose cycle and pyruvate dehydrogenase in the rat ventral prostate.  J Steroid Biochem Mol Biol. 1981;  14 1075-1084
  • 21 Costello L C, Franklin R B. Testosterone regulates pyruvate dehydrogenase activity of prostate mitochondria.  Horm Metab Res. 1993;  25 268-270
  • 22 Costello L C, Franklin R B, Liu Y. Testosterone regulates pyruvate dehydrogenase E1α in prostate.  Endocrine J. 1994;  2 147-151
  • 23 Costello L C, Liu Y, Zou J, Franklin R B. The pyruvate dehydrogenase E1α gene is regulated by testosterone and prolactin in prostate epithelial cells.  Endocrine Res. 2000;  26 23-29
  • 24 Costello L C, Liu Y, Franklin R B. Testosterone stimulates the biosynthesis of m-aconitase in prostate epithelial cells.  Cell Mol Endocrinol. 1995;  112 45-51
  • 25 Franklin R B, Juang H H, Zou J, Costello L C. Regulation of citrate metabolism by androgen in human prostate carcinoma cells.  Endocrine J. 1995;  3 603-607
  • 26 Costello L C, Liu Y, Franklin R B. Testosterone and prolactin stimulation of m-aconitase in pig prostate epithelial cells.  Urology. 1996;  48 654-659
  • 27 Costello L C, Liu Y, Zou J, Franklin R B. Mitochondrial aconitase gene expression is regulated by testosterone and prolactin in prostate epithelial cells.  Prostate. 2000;  42 196-202
  • 28 Rui H, Purvis K. Hormonal control of prostate function.  Scand J Urol Nephrol Suppl. 1988;  107 32-38
  • 29 Grayhack J T, Lebowitz A. Effect of prolactin on citric acid of lateral lobe of prostate of Sprague-Dawley rats.  Invest Urol. 1967;  5 7-94
  • 30 Grayhack J T. Effect of testosterone, estradiol administration on citric acid and fructose content of the rat prostate.  Endocrinol. 1965;  77 1068-1074
  • 31 Rui H, Purvis K. Independent control of citrate production and ornithine decarboxylase by prolactin in the lateral lobe of the rat.  Mol Cell Endocrinol. 1987;  52 91-95
  • 32 Franklin R B, Costello L C. Prolactin directly stimulates citrate production and mAAT of prostate epithelial cells.  Prostate. 1990;  17 13-18
  • 33 Arunakaran J, Aruldhas M M, Govindarajulu P. Effect of prolactin and androgens on the prostate of bonnet monkeys, macaca radiata: I. nucleic acids phosphatases and citric acid.  Prostate. 1987;  10 265-273
  • 34 Franklin R B, Zou J, Gorski E, Yang Y H, Costello L C. Prolactin regulation of mAAT and PKC in human prostate cancer cells.  Mol Cell Endocrinol. 1997;  127 19-25
  • 35 Gorski E, Zou J, Costello L C, Franklin R B. Protein kinase C mediates prolactin regulation of mitochondrial aspartate aminotransferase gene expression in prostate cells.  Molecular Urol. 1999;  3 17-23
  • 36 Franklin R B, Ekiko D B, Costello L C. Prolactin stimulates transcription of aspartate aminotransferase in prostate cells.  Mol Cell Endocrinol. 1992;  90 27-32
  • 37 Costello L C, Franklin R B, Liu Y. Prolactin specifically increases PDH E1α in rat lateral prostate epithelial cells.  Prostate. 1995;  26 189-193
  • 38 Liu Y, Costello L C, Franklin R B. Prolactin specifically regulates citrate oxidation and m-aconitase of prostate epithelial cells.  Metabolism. 1996;  45 442-449
  • 39 Roche P J, Hoare S E, Parker M G. A consensus DNA binding site for the androgen receptor.  Mol Endocrinol. 1992;  6 2229-2235
  • 40 Zhou Z, Corden J L, Brown T R. Identification and characterization of a novel androgen response element composed of a direct repeat.  J Biol Chem. 1997;  272 8227-8235
  • 41 Cleutjens K B, van Eekelen C C, van der Korput H A, Brinkmann A O, Trapman J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate specific antigen promoter.  J Biol Chem. 1996;  271 6379-6388
  • 42 Dai J L, Burnstein K L. Two androgen response elements in the androgen receptor coding region are required for cell-specific up-regulation of receptor messenger RNA.  Mol Endocrinol. 1996;  10 1582-1594
  • 43 Claessens F, Alen P, Devos A, Peeters B, Verhoeven G, Rombauts W. The androgen-specific probasin response element 2 interacts differentially with androgen and glucocorticoid receptors.  J Biol Chem. 1996;  271 19 013-19 016
  • 44 Claessens F, Verrijdt G, Schoenmakers E, Haelens A, Peeters B, Verhoeven G, Rombauts W. Selective DNA binding by the androgen receptor as a mechanism for hormone-specific gene regulation.  J Steroid Biochem Mol Biol. 2001;  76 23-30
  • 45 Larrea F, Sanchez-Gonzalez S, Mendez I, Garcia-Becerra R, Cabrera V, Ulloa-Aguirre A. G protein-coupled receptors as targets for prolactin actions.  Arch Med Res. 1999;  30 532-543
  • 46 Bole-Feysot C, Goffin V, Edery M, Binart N. Prolactin and its receptor. Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice.  Endocrine Rev. 1998;  19 225-268
  • 47 Franklin R B, Zou J, Ma J, Costello L C. Protein kinase C alpha, epsilon and AP-1 mediate prolactin regulation of mitochondrial aspartate aminotransferase expression in the rat lateral prostate.  Mol Cell Endocrinol. 2000;  170 153-162
  • 48 Xu Y-H, Horseman N D. Nuclear proteins and prolactin-induced annesin Icp35 gene transcription.  Mol Endocrinol. 1992;  6 375-383
  • 49 Carey G B, Liberti J P. Stimulation of receptor-associated kinase, tyrosine kinase, and MAP kinase is required for prolactin mediated macromolecular biosynthesis and mitogenesis in Nb2 lymphoma.  Arch Biochem Biophys. 1995;  316 179-189
  • 50 Crowe P D, Buckley A R, Zorn N E, Rui H. Prolactin activates protein kinase C and stimulates growth-related gene expression in rat liver.  Mol Cell Endocrinol. 1991;  79 29-35
  • 51 Ciereszko R E, Petroff B K, Ottobre A C, Guan Z, Stokes B T, Ottobre J S. Assessment of the mechanism by which prolactin simulates progesterone production by early corpora lutea of pigs.  J Endocrinol. 1998;  159 201-209
  • 52 Peters C A, Maizels E T, Robertson M C, Shiu R PC, Soloff M S, Hunzicker-Dunn M. Induction of relaxin messenger RNA expression in response to prolactin receptor activation requires protein kinase C delta signaling.  Mol Endocrinol. 2000;  14 576-590
  • 53 Ahonen T J, Harkonen P L, Rui H, Nevaleinen M T. PRL signaling in the epithelial cell compartment of rat prostate maintained as long-term organ cultures in vitro.  Endocrinol. 2002;  143 228-238
  • 54 Harkonen P L, Isoltalo A, Santti R. Studies on the mechanism of testosterone action on glucose metabolism in the rat ventral prostate.  J Steroid Biochem Mol Biol. 1975;  6 1405-1413
  • 55 Franklin R B, Lao L, Costello L C. Evidence for two aspartate transport systems in prostate epithelial cells.  Prostate. 1990;  16 137-146
  • 56 Lao L, Franklin R B, Costello L C. A high affinity L-aspartate transporter in prostate epithelial cells which is regulated by testosterone.  Prostate. 1993;  22 53-63
  • 57 Lao L. Characteristics and regulation of aspartate transport systems in rat ventral prostate epithelial cells. Ph.D. Thesis Dissertation (RB Franklin and LC Costello, thesis advisors). University of Maryland 1992: 144
  • 58 Liu Y, Costello L C, Franklin R B. Prolactin and testosterone regulation of mitochondrial zinc in prostate epithelial cells.  Prostate. 1997;  30 26-32
  • 59 Costello L C, Liu Y, Zou J, Franklin R B. Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone.  J Biol Chem. 1999;  274 17 499-17 504

L. Costello, Ph.D.

OCBS/Dental School

666 West Baltimore Street · Baltimore · Maryland 21201 · USA

Phone: + 1 (410) 706 76 18

Fax: + 1 (410) 706 76 18

Email: lcc001@dental.umaryland.edu