Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells

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 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.

Fig. 1

The pathway of net citrate production in prostate secretory epithelial cells. The key regulatory enzymes are represented in the rectangles. PDH, pyruvate dehydrogenase; CS, citrate synthase; mAAT, mitochondrial aspartate aminotransferase; ACON, aconitase; GDH, glutamate dehydrogenase.

Fig. 2

The mechanism of testosterone regulation of the metabolic genes as represented by regulation of mAAT. (1) Testosterone enters the cell and is reduced to dihydrotestosterone (DHT); (2) DHT combines with androgen receptor (AR); (3) the DHT-AR complex undergoes a conformational change followed by (4) dimerization; the activated AR dimer binds to the androgen response elements (ARE 1 and 2) located in proximity of the basal transcription complex (BTC) of the mAAT gene; (6) transcription of mAAT is stimulated which leads to (7) the biosynthesis of pre-mAAT; (8) pre-mAAT is translocated to the mitochondria where it is processed to the active form of mAAT.

Fig. 3

The hormone regulatory region of the mAAT gene.

Fig. 4

The mechanism of prolactin regulation of the metabolic genes and citrate production in prostate cells as represented by regulation of mAAT. Prolactin combines with its receptor. The PRL-R complex couples to a plasma membrane component (?, unknown) which activates phospholipase c (PLC) leading to the formation of diacylglycerol (DG) and inositoltriphosphate (IP3) and the conversion of inactive PKC to membrane-bound active PKC. PKC phosphorylates cytosolic transcription factor (?, unknown) that leads to the formation of AP1 from existing protein (fos/jun). AP1 binds to its activation sites (that is, TRE = TPA response element) located in the regulatory region of the mAAT gene (see Fig. 3); mAAT gene transcription is increased leading to the biosynthesis of mAAT. Increased mAAT increases the production of OAA (oxalacetate) that is required for citrate synthesis.