Regulation of citrate metabolism by androgen in the LNCaP human prostate carcinoma cell line

Franklin, Renty B.; Juang, Horng‐Heng; Zou, Jing; Costello, Leslie C.

doi:10.1007/bf02953026

Cited by 17 publications

(18 citation statements)

References 21 publications

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“…As presented under "Results," both cell lines exhibit the capability of accumulating high zinc levels under the in vitro conditions employed; therefore, they are excellent models for studying the mechanisms and regulation of zinc accumulation. Moreover, LNCaP cells exhibit the characteristics of citrate-producing cells with a limiting m-aconitase, whereas PC-3 cells are citrate-oxidizing cells in which m-aconitase is not limiting (13). In addition, LNCaP cells have a very low tumorigenicity compared with the highly tumorigenic PC-3 cells.…”

Section: Methodsmentioning

confidence: 99%

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Evidence for a Zinc Uptake Transporter in Human Prostate Cancer Cells Which Is Regulated by Prolactin and Testosterone

Costello

Liu

Zou

et al. 1999

Journal of Biological Chemistry

204

135

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The glandular epithelial cells of the human prostate gland have the unique capability and function of accumulating the highest zinc levels of any soft tissue in the body. Zinc accumulation in the prostate is regulated by prolactin and testosterone; however, little information is available concerning the mechanisms associated with zinc accumulation and its regulation in prostate epithelial cells. In the present studies the uptake and accumulation of zinc were determined in the human malignant prostate cell lines LNCaP and PC-3. The results demonstrate that LNCaP cells and PC-3 cells possess the unique capability of accumulating high levels of zinc. Zinc accumulation in both cell types is stimulated by physiological concentrations of prolactin and testosterone. The studies reveal that these cells contain a rapid zinc uptake process indicative of a plasma membrane zinc transporter. Initial kinetic studies demonstrate that the rapid uptake of zinc is effective under physiological conditions that reflect the total and mobile zinc levels in circulation. Correspondingly, genetic studies demonstrate the expression of a ZIP family zinc uptake transporter in both LNCaP and PC-3 cells. The rapid zinc uptake transport process is stimulated by treatment of cells with physiological levels of prolactin and testosterone, which possibly is the result of the regulation of the ZIP-type zinc transporter gene. These zincaccumulating characteristics are specific for prostate cells. The studies support the concept that these prostate cells express a unique hormone-responsive, plasma membrane-associated, rapid zinc uptake transporter gene associated with their unique ability to accumulate high zinc levels.Zinc is an essential component of all cells. It is required for a variety of cellular activities such as metalloenzyme activity, nucleoprotein and nucleic acid structure, and transcription factor interactions. Typically, intracellular zinc is found predominantly (Ͼ 95%) bound to high molecular weight ligands such as metalloenzymes, metalloproteins, nucleoproteins, and nucleic acids. Very little zinc is available as free or loosely bound zinc, which we will refer to as " mobile reactive zinc" (for review, see Refs. 1-3).The prostate gland of humans and other animals is unique in that it accumulates much higher zinc levels than any other soft tissues in the body. For detailed and extensive reviews of zinc-citrate relationships in prostate, see Refs. 4 -6. The special functions associated with the high zinc level of the prostate have not been resolved. The ability of the prostate to accumulate high zinc levels is a function of the glandular secretory epithelial cells. Our recent studies (7) with rat prostate lobes have demonstrated that the epithelial cells contain high levels of intracellular zinc, and, most importantly, contain high levels of mitochondrial zinc. The accumulation of zinc results in the inhibition of mitochondrial aconitase activity which minimizes the ability of these cells to oxidize citrate (8). This is an important r...

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Section: Methodsmentioning

confidence: 99%

“…The conditions for culture and harvesting of the cells were the same as described previously (13). The culture medium was RPMI 1640 and 10% fetal bovine serum (FBS).…”

Section: Methodsmentioning

confidence: 99%

Evidence for a Zinc Uptake Transporter in Human Prostate Cancer Cells Which Is Regulated by Prolactin and Testosterone

Costello

Liu

Zou

et al. 1999

Journal of Biological Chemistry

204

135

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show abstract

“…This is achieved by testosterone stimulation of m-aconitase gene expression that leads to increased biosynthesis of m-aconitase enzyme and increased aconitase enzyme activity [24][25][26][27]. Seemingly, an increase in citrate oxidation would be antithetical to the testosterone effect in increasing net citrate production.…”

Section: Testosterone Regulation Of Citrate Oxidationmentioning

confidence: 99%

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

Costello

Franklin

2002

Horm Metab Res

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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.

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“…This suggests that vitamin D and androgen supplementation facilitate the reversion of the metabolic switch that occurs during prostate carcinogenesis by preventing citrate oxidation, partially restoring the normal prostatic function and shunting citrate into the cytoplasm for secretion and lipid synthesis (Figure 3). This is supported by the observation that LNCaP cells retain the sensitivity to androgen-induced citrate production and accumulation (Franklin et al, 1995). This suggests that vitamin D facilitates and maintains this differentiated phenotype, rendering prostate cancer cells less aggressive.…”

Section: Intermediate Metabolism: the Warburg Effectmentioning

confidence: 78%

Vitamin D, intermediary metabolism and prostate cancer tumor progression

Wang

Tenniswood

2014

Front. Physiol.

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Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways.

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Regulation of citrate metabolism by androgen in the LNCaP human prostate carcinoma cell line

Cited by 17 publications

References 21 publications

Evidence for a Zinc Uptake Transporter in Human Prostate Cancer Cells Which Is Regulated by Prolactin and Testosterone

Evidence for a Zinc Uptake Transporter in Human Prostate Cancer Cells Which Is Regulated by Prolactin and Testosterone

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

Vitamin D, intermediary metabolism and prostate cancer tumor progression

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