Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer cells are known to express cyclooxygenases (COXs) and synthesize prostaglandins. Catabolism of prostaglandins in these cells remains to be determined. Induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key metabolic inactivation enzyme, was investigated in androgen-sensitive LNCaP cells and in hormone-independent PC3 cells. 15-PGDH was found to be induced by dihydrotestosterone or testosterone in a time- and dose-dependent manner in LNCaP but not in PC3 cells as shown by activity assay and immunoblot analysis. However, prostaglandin synthetic enzymes, COX-1 and COX-2, were not found to be induced by androgens. Induction was also achieved by 17beta-estradiol and progesterone, although to a lesser extent. Induction of 15-PGDH was not blocked by steroid receptor antagonist, RU 486, nor by antiandrogen, flutamide. However, induction was inhibited by tyrosine kinase inhibitor, genistein, and by ERK kinase inhibitor, PD 98059, but not by protein kinase C inhibitor, GF109203X. These results suggest that androgens induce 15-PGDH gene expression through an unconventional nongenomic pathway.
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PMID:Induction of NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase expression by androgens in human prostate cancer cells. 1100 85

NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD(+)-dependent oxidation of prostaglandins and other nonprostanoid compounds. This enzyme was found to be dramatically induced in hormone-responsive human prostate cancer cells by androgens [M. Tong, and H. H. Tai, 2000, Biochem. Biophys. Res. Commun. 276, 77-81] and could be involved in prostate tumorigenesis. Inhibitors of this enzyme may be of value in determining the utility of these compounds in cancer chemoprevention. Previously, ciglitazone, an antidiabetic thiazolidinedione, was found to be a potent inhibitor of 15-PGDH. Structure-activity analysis of available thiazolidinediones indicated that the nature of the moiety linking to phenyl ring through ether linkage and benzylidene configuration play important roles in inhibitory potency. Furthermore, N-methylation of 2,4-thiazolidinedione abolished the inhibitory activity. A series of benzylidene thiazolidinediones with varied ring structure and methylene bridge to phenyl ring through ether linkage were synthesized and assayed for inhibitory activity. It was found that compound CT-8 (5-[4-(cyclohexylethoxy)benzylidene]-2,4-thiazolidinedione) was the most potent inhibitor effective at nanomolar range. Kinetic studies revealed that inhibition by this compound was noncompetitive with respect to NAD(+) and uncompetitive with respect to prostaglandin E(2), indicating that the inhibitor interacts with the enzyme at a site distinct from the substrate binding site. This regulatory site appears to overlap with the activator site occupied by imipramine since activation of the enzyme by this activator is competitively inhibited by compound CT-8.
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PMID:Thiazolidinediones as a novel class of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase inhibitors. 1222 May 39

Human prostate cancer is characterized by an early and near-universal loss of expression of the phase 2 enzyme glutathione S-transferase-pi (GSTP1). We hypothesize that a mechanism-based prostate cancer preventive strategy could involve induction of phase 2 enzymes within the prostate to compensate for the loss of GSTP1 expression. NAD[P]H:(quinone-acceptor) oxidoreductase (quinone reductase or QR) enzymatic activity, a surrogate of phase 2 enzyme response, was measured after treating the human prostate cancer cell line LNCaP with known phase 2 enzyme-inducing agents from 10 distinct chemical classes. QR enzymatic activity was assayed in microtiter plates using the menadione-coupled reduction of tetrazolium dye. Degree of induction was expressed as fold-increase over control and corrected for toxicity. Compounds were also tested in LNCaP-5-aza-C, an LNCaP subline selected in 5-aza-cytidine that expresses GSTP1, and in the human liver cell line HepG2. LNCaP showed robust induction of QR enzymatic activity after treatment with a subset of the phase 2 enzyme-inducing agents. All Michael acceptors were effective at inducing QR activity in LNCaP. Some phenolic antioxidants, heavy metal salts, and quinones also significantly increased QR activity, although inducer potency varied widely within these classes of compounds. Some of the isothiocyanates, mercaptans, bifunctional inducers, and trivalent arsenicals also produced modest QR induction, but peroxides and dithiolethiones were inactive. LNCaP-5-aza-C and LNCaP responded similarly to all compounds, but the pattern of response for HepG2 differed significantly. The differences in QR responsiveness between the prostate cell lines and HepG2 suggest that prostate tissues may have a unique pattern of response to phase 2-inducing agents distinct from other tissue types. Our data suggest that measurement of QR induction in prostate cancer cell lines may help identify potential cancer chemopreventive agents effective in the prostate.
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PMID:Identification of potential prostate cancer preventive agents through induction of quinone reductase in vitro. 1222 31

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD(+)-dependent oxidation of 15(S)-hydroxyl group of prostaglandins and has been considered a key enzyme involved in biological inactivation of prostaglandins. This enzyme is markedly induced by androgens in hormone-sensitive human prostate cancer cells (Tong M., Tai H. H. Biochem Biophys Res Commun 2000; 276: 77-81) and may be involved in tumorigenesis. Inhibition of this enzyme may be of value in anticancer therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit cyclooxygenases (COXs) have been shown to be chemopreventive in epidemiological and animal-model studies. However, chemoprevention by these drugs may not be directly related to their inhibition of COXs. Other targets may be also involved in their chemopreventive activity. We have examined a variety of NSAIDs including COX-2 selective inhibitors, peroxisome proliferator-activated receptor (PPAR) gamma agonists and phytophenolic compounds which have been shown to be chemopreventive for their effect on 15-PGDH. It was found that most of these compounds were potent inhibitors of 15-PGDH. Among these compounds, ciglitazone appeared to be the most powerful inhibitor (IC(50)=2.7 microM). Inhibition by ciglitazone was non-competitive with respect to NAD(+) and uncompetitive with respect to PGE(2).
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PMID:Inhibition of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by cyclooxygenase inhibitors and chemopreventive agents. 1246 68

The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play an important role in the regulation of steroid hormones, such as estrogens and androgens, by catalysing the reduction of 17-ketosteroids or the oxidation of 17beta-hydroxysteroids using NAD(P)H or NAD(P)(+) as cofactor. The enzyme activities associated with the different 17beta-HSD isoforms are widespread in human tissues, not only in classic steroidogenic tissues, such as the testis, ovary, and placenta, but also in a large series of peripheral intracrine tissues. In the nineties, several new types of 17beta-HSD were reported, indicating that a fine regulation is carried out. More importantly, each type of 17beta-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution. These findings are important for understanding the mode of action of the 17beta-HSD family. From a therapeutic point of view, this means that selectivity of drug action could be achieved by targeting a particular 17beta-HSD isozyme. Consequently, each study that leads to better knowledge of the inhibition of 17beta-HSDs deserves attention from scientists working in this and related fields. Being involved in the last step of the biosynthesis of sex steroids from cholesterol, the 17beta-HSD family constitutes an interesting target for controlling the concentration of estrogens and androgens. Thus, inhibitors of 17beta-HSDs are useful tools to elucidate the role of these enzymes in particular biological systems or for a therapeutic purpose, especially to block the formation of active hydroxysteroids that stimulate estrogeno-sensitive pathologies (breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Few review articles have however focussed on 17beta-HSD inhibitors although this family of steroidogenic enzymes includes interesting therapeutic targets for the control of several diseases. Furthermore, inhibitors of 17beta-HSDs constitute a growing field in biomedical research and there is a need for an exhaustive review on this topic. In addition to giving an up-to-date description of inhibitors of all 17beta-HSD isoforms (types 1-8), the present review will also address, when possible, the isoform selectivity and residual estrogenic or androgenic activity often associated with steroidal inhibitors.
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PMID:Inhibitors of 17 beta-hydroxysteroid dehydrogenases. 1257 Jun 93

Human aldo-keto reductases (AKRs) of the AKR1C subfamily function in vitro as 3-keto-, 17-keto-, and 20-ketosteroid reductases or as 3alpha-, 17beta-, and 20alpha-hydroxysteroid oxidases. These AKRs can convert potent sex hormones (androgens, estrogens, and progestins) into their cognate inactive metabolites or vice versa. By controlling local ligand concentration AKRs may regulate steroid hormone action at the prereceptor level. AKR1C2 is expressed in prostate, and in vitro it will catalyze the nicotinamide adenine dinucleotide (NAD(+))-dependent oxidation of 3alpha-androstanediol (3alpha-diol) to 5alpha-dihydrotestosterone (5alpha-DHT). This reaction is potently inhibited by reduced NAD phosphate (NADPH), indicating that the NAD(+): NADPH ratio in cells will determine whether AKR1C2 makes 5alpha-DHT. In transient COS-1-AKR1C2 and in stable PC-3-AKR1C2 transfectants, 5alpha-DHT was reduced by AKR1C2. However, the transfected AKR1C2 oxidase activity was insufficient to surmount the endogenous 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity, which eliminated 3alpha-diol as androsterone. PC-3 cells expressed retinol dehydrogenase/3alpha-HSD and 11-cis-retinol dehydrogenase, but these endogenous enzymes did not oxidize 3alpha-diol to 5alpha-DHT. In stable LNCaP-AKR1C2 transfectants, AKR1C2 did not alter androgen metabolism due to a high rate of glucuronidation. In primary cultures of epithelial cells, high levels of AKR1C2 transcripts were detected in prostate cancer, but not in cells from normal prostate. Thus, in prostate cells AKR1C2 acts as a 3-ketosteroid reductase to eliminate 5alpha-DHT and prevents activation of the androgen receptor. AKR1C2 does not act as an oxidase due to either potent product inhibition by NADPH or because it cannot surmount the oxidative 17beta-HSD present. Neither AKR1C2, retinol dehydrogenase/3alpha-HSD nor 11-cis-retinol dehydrogenase is a source of 5alpha-DHT in PC-3 cells.
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PMID:Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells. 1281 May 47

Little is known about the roles of androgens in the regulation of redox state in the prostate, a cellular process believed to profoundly influence normal and aberrant prostate functions. We demonstrate that castration induced discrete oxidative stress (OS) in the acinar epithelium of rat ventral prostate (VP), as evident from marked increases in 8-hydroxy-2'-deoxy-guanosine and 4-hydroxynonenal protein adducts in the regressing epithelium. Testosterone replacement partially reduced OS in VP epithelia of castrates, but the level remained higher than in intact rats. Quantification of steady-state mRNA levels of 14 genes involved in the anabolism and catabolism of reactive oxygen species (ROS) showed that castration resulted in dramatic increases of three ROS-generating NAD(P)H oxidases (Noxs) including Nox1, gp91(phox), and Nox4, significant reductions of key ROS-detoxifying enzymes (superoxide dismutase 2, glutathione peroxidase 1, thioredoxin, and peroxiredoxin 5), and unchanged levels of catalase, glutathione reductase, gamma-glutamyl transpeptidase, and glutathione synthetase. Testosterone replacement in castrated rats partially reduced expression of Noxs but restored expression of superoxide dismutase 2, glutathione peroxidase 1, thioredoxin, and peroxiredoxin 5 to complete normalcy and induced a compensatory increase in expression of catalase, glutathione reductase, gamma-glutamyl transpeptidase, and glutathione synthetase in the regenerating VP. Expression of superoxide dismutase 1, glutathione S-transferase-pi, and glucose-6-phosphate dehydrogenase was unaffected by castration and testosterone replacement. These findings indicate androgen-deprivation induces OS in the rat VP through elevation of ROS anabolism and diminution of antioxidant detoxification. Androgen replacement partially reduces OS in rat VP to precastration levels. Expression of Noxs remained high amid a broad-based recovery of antioxidant defense mechanism(s). These data might have implications on the use of androgen blockade for prostate cancer prevention and androgen therapy for andropause treatment in elderly men.
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PMID:Androgenic regulation of oxidative stress in the rat prostate: involvement of NAD(P)H oxidases and antioxidant defense machinery during prostatic involution and regrowth. 1463 23

Human type 10 17beta-hydroxysteroid dehydrogenase (HSD) is a homotetrameric protein located in mitochondria. This enzyme was alternatively named short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHSD). This NAD(H)-dependent dehydrogenase is essential for the metabolism of branched-chain fatty acids and isoleucine, and is expressed in a variety of tissues, e.g., prostate, brain, liver, and heart. This enzyme inactivates 17beta-estradiol and exhibits a strong oxidative 3alpha-HSD activity to convert 5alpha-androstanediol and allopregnanolone into 5alpha-dihydrotestosterone (5alpha-DHT) and 5alpha-dihydroprogesterone, respectively, in living cells. Certain malignant prostatic epithelial cells and activated astrocytes in Alzheimer's disease patient's brain contain extraordinarily high levels of this enzyme. This mitochondrial dehydrogenase enables prostate cancer cells to generate 5alpha-DHT in the absence of testosterone. Its inactivation of allopregnanolone is important to the modulation of GABA(A) receptor. Among steroidogenic enzymes 17beta-HSD10 plays a significant part in the intracrinology. Although this protein has an affinity for amyloid-beta peptide, its role in the pathogenesis of Alzheimer's disease is far from clear. Additional knowledge of this versatile enzyme would provide the foundation for designing new drugs aimed at treating some neurological diseases and certain types of cancers.
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PMID:Roles of type 10 17beta-hydroxysteroid dehydrogenase in intracrinology and metabolism of isoleucine and fatty acids. 1661 Nov 67

The NAD-dependent histone deacetylase Sir2 plays a key role in connecting cellular metabolism with gene silencing and aging. The androgen receptor (AR) is a ligand-regulated modular nuclear receptor governing prostate cancer cellular proliferation, differentiation, and apoptosis in response to androgens, including dihydrotestosterone (DHT). Here, SIRT1 antagonists induce endogenous AR expression and enhance DHT-mediated AR expression. SIRT1 binds and deacetylates the AR at a conserved lysine motif. Human SIRT1 (hSIRT1) repression of DHT-induced AR signaling requires the NAD-dependent catalytic function of hSIRT1 and the AR lysine residues deacetylated by SIRT1. SIRT1 inhibited coactivator-induced interactions between the AR amino and carboxyl termini. DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins.
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PMID:Hormonal control of androgen receptor function through SIRT1. 1692 62

The endocrine signaling governing nuclear receptor (NR) function has been known for several decades to play a crucial role in the onset and progression of several tumor types. Notably among these are the estrogen receptor (ER) in breast cancer and androgen receptor (AR) in prostate cancer. Other nuclear receptors may be involved in cancer progression including the peroxisome-proliferator activating receptor gamma (PPARgamma), which has been implicated in breast, thyroid, and colon cancers. These NR are phylogenetically conserved modular transcriptional regulators, which like histones, undergo post-translational modification by acetylation, phosphorylation and ubiquitination. Importantly, the transcriptional activity of the receptors is governed by the coactivator p300, the activity of which is thought to be rate-limiting in the activity of these receptors. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), modify histones by adding or removing an acetyl group from the epsilon amino group of lysines within an evolutionarily conserved lysine motif. Histone acetylation results in changes in chromatin structure in response to specific signals. These enzymes can also directly catalyze the NRs themselves, thus modifying signals at the receptor level. The post-translational modification of NR which is regulated by hormones, alters the NR function toward a growth promoting receptor. The deacetylation of NR is mediated by TSA-sensitive and NAD-dependent deacetylases. The regulation of NR by NAD-dependent enzymes provides a direct link between intracellular metabolism and hormone signaling.
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PMID:The functional significance of nuclear receptor acetylation. 1729 55


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