Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells.
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 possess 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 dehydrogenase, 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.
Costello
L C
LC
Molecular and Cellular Biology Section, OCBS/Dental School, University of Maryland, Baltimore, Maryland 21201, USA. lcc@dental.umaryland.edu
Franklin
R B
RB
D000818:Animals; D002951:Citrates / Q000096:biosynthesis / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D011388:Prolactin / Q000494:pharmacology*; D011467:Prostate / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*
D002951:Citrates; D013739:Testosterone; D011388:Prolactin