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)

Human or rat microsomal 5 alpha-reductase activity, as measured by enzymic conversion of testosterone into 5 alpha-dihydrotestosterone or by binding of a competitive inhibitor, [3H]17 beta-NN-diethulcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one ([3H]4-MA) to the reductase, is inhibited by low concentrations (less than 10 microM) of certain polyunsaturated fatty acids. The relative inhibitory potencies of unsaturated fatty acids are, in decreasing order: gamma-linolenic acid greater than cis-4,7,10,13,16,19-docosahexaenoic acid = cis-6,9,12,15-octatetraenoic acid = arachidonic acid = alpha-linolenic acid greater than linoleic acid greater than palmitoleic acid greater than oleic acid greater than myristoleic acid. Other unsaturated fatty acids such as undecylenic acid, erucic acid and nervonic acid, are inactive. The methyl esters and alcohol analogues of these compounds, glycerols, phospholipids, saturated fatty acids, retinoids and carotenes were inactive even at 0.2 mM. The results of the binding assay and the enzymic assay correlated well except for elaidic acid and linolelaidic acid, the trans isomers of oleic acid and linoleic acid respectively, which were much less active than their cis isomers in the binding assay but were as potent in the enzymic assay. gamma-Linolenic acid had no effect on the activities of two other rat liver microsomal enzymes: NADH:menadione reductase and glucuronosyl transferase. gamma-Linolenic acid, the most potent inhibitor tested, decreased the Vmax. and increased Km values of substrates, NADPH and testosterone, and promoted dissociation of [3H]4-MA from the microsomal reductase. gamma-Linolenic acid, but not the corresponding saturated fatty acid (stearic acid), inhibited the 5 alpha-reductase activity, but not the 17 beta-dehydrogenase activity, of human prostate cancer cells in culture. These results suggest that unsaturated fatty acids may play an important role in regulating androgen action in target cells.
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PMID:Inhibition of steroid 5 alpha-reductase by specific aliphatic unsaturated fatty acids. 163 46

Incubation of whole LNCaP cells in suspension with tritium labeled cortisol revealed two major and one minor radioactive product. Of the major products, one migrated with an Rf value identical to cortisol (Kendall's compound "F"), and the second migrated with an Rf value similar to nonradioactive cortisone (Kendall's compound "E"); the third minor product comigrated with 21-acetylated cortisol. The conversion of cortisol to cortisone was linear with respect to cell number, and conversion reached a plateau after 120 min of incubation at 37 degrees C. One half of the cortisol was converted to cortisone within 2 h of incubation at 37 degrees C. This conversion was nicotine amide dinucleotide (NAD) dependent. Low levels of transcription activation by cortisol were documented in LNCaP cells transfected with glucocorticoid and androgen responsive mouse mammary tumor virus-bacterial chloramphenicol acetyltransferase chimeric gene (MMTV-CAT). Hormone binding assay and transactivation analysis revealed the presence of a functional mineralocorticoid receptor in LNCaP cells. Treatment of transfectants with F in the presence of carbenoxolone, a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), resulted in a two orders of magnitude increase in measurable CAT activity. The addition of the reduced form of nicotine amide dinucleotide (NADH) in the presence of 10(-7) M E stimulated measurable CAT activity in LNCaP cells. In conferring aldosterone specificity in mineralocorticoid target tissues, 11 beta-HSD may have an important role as "gate keeper" in allowing a specific androgen response in hormone responsive LNCaP prostate cancer cells.
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PMID:11 beta-Hydroxysteroid dehydrogenase and tissue specificity of androgen action in human prostate cancer cell LNCaP. 803 14

The purpose of this study was to investigate the role of superoxide anion (02-*) in the regulation of p53 or c-Ha-ras expression and proliferation in the prostate cancer cell line PC3. Cell proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence of O2-*, basic fibroblast growth factor (bFGF) or their combination. p53 or C-Ha-ras expression in the cells treated with O2-* was assayed by fluorescence in situ hybridization (FISH). The proliferation was significantly inhibited by O2-* in a concentration-dependent manner ranging from 9 to 36 micromol/l nicotinamide adenine dinucleotid (NADH) combined with 2-8 micromol/l N-methylphenazonium methyl sulfate (PMS). Enhancement of proliferation by 2 ng/ml bFGF was significantly inhibited by O2-*. Although O2-* was not able to alter c-Ha-ras gene expression, O2-* at the concentrations of 18 micromol/l NADH and 4 micromol/l PMS upregulated the expression of p53. O2-* may modulate proliferation and gene expression in PC3 cells.
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PMID:Role of superoxide anion on the proliferation and c-Ha-ras or p53 expression in prostate cancer cell line PC3. 984 Mar 45

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a well-studied glycolytic enzyme that plays a key role in energy metabolism. GAPDH catalyzes the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate in the glycolytic pathway. As part of the conversion, GAPDH converts NAD+ to the high-energy electron carrier NADH. GAPDH has been referred to as a "housekeeping" protein and based on the view that GAPDH gene expression remains constant under changing cellular conditions, the levels of GAPDH mRNA have frequently been used to normalize northern blots. In recent years, that view has changed since GAPDH is now known to contribute to a number of diverse cellular functions unrelated to glycolysis. Normative functions of GAPDH now include nuclear RNA export, DNA replication, DNA repair, exocytotic membrane fusion, cytoskeletal organization and phosphotransferase activity. Pathologically, GAPDH has been implicated in apoptosis, neurodegenerative disease, prostate cancer and viral pathogenesis (see Sirover (1999) for a recent review of GAPDH functions). Most recently, it has been shown that GAPDH is a target for deprenyl related compounds (Carlile et al., 2000; Kragten et al., 1998) and may contribute to the neuroprotection offered by those compounds.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. 1120 59

We recently demonstrated the existence of specific patterns of somatic mitochondrial DNA (mtDNA) mutations in several cancers. Here we sought to identify the presence of mtDNA mutations in prostate cancer and their paired PIN lesions. The D-loop region, 16S rRNA, and the NADH subunits of complex I were sequenced to identify mtDNA mutations in 16 matched PIN lesions and primary prostate cancers. Twenty mtDNA mutations were detected in the tumor tissue of three patients. Identical mutations were also identified in the PIN lesion from one patient. This patient with multiple point mutations also harbored a high frequency of microsatellite instability (MSI-H) in nuclear mononucleotide repeat markers. Remarkably, identical mutations were also detected in all (3/3) matched urine and plasma samples obtained from these patients. Although mitochondrial mutations are less common in prostate adenocarcinoma, they occur early in cancer progression and they can be detected in bodily fluids of early stage disease patients. The identification of MtDNA mutations may complement other early detection approaches for prostate cancer.
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PMID:Mitochondrial mutations in early stage prostate cancer and bodily fluids. 1152 8

The purpose of this study was to investigate the role of superoxide anion(O2-) in the regulation of epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) expression and proliferation in the prostate cancer cell line PC3. Cell proliferation was tested by a 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay in the presence of O2-, EGF or their combination. Immunohistochemistry was carried out to assay the expression of EGF or EGFR. EGF or EGFR mRNA expression in the cells treated with O2- was examined by in situ hybridisation. The proliferation was significantly inhibited by O2- in a concentration-dependent manner ranging from 9 to 36 micromol/l nicotinamide adenine dinucleotide (NADH) combined with 2-8 micromol/l N-methylphenazonium methyl sulfate (PMS). The enhancement of proliferation induced by 5 ng/ml EGF was significantly overcome by O2-. Although O2- was not able to alter EGFR mRNA expression, O2- at the concentration of 18 micromol/l NADH and 4 micromol/l PMS reduced EGFR protein expression. O2- at the concentration of 18 micromol/l NADH and 4 micromol/l PMS can downregulate EGF and EGF mRNA expression.
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PMID:The role of superoxide anion in the regulation of epidermal growth factor or the expression and proliferation of its receptor in prostate cancer cell line PC3. 1194 25

The metabolic organization of both normal and malignant prostate cellular phenotypes involves some unusual and surprising features. In particular, both conditions exhibit ratios of NADH/NAD+ and NADPH/NADP+ characteristic of high oxidative states despite a chronic shortage of O2 in both conditions. In this paper, we observe that, in prostate cancer cells, the oxidizing power of the fatty acid synthesis (FAS) pathway is so large that redox is stabilized more favorably (more oxidized) than in normal prostate cells. This FAS-facilitated redox improvement occurs despite the fact that malignant cells are more O2 limited and therefore express more hypoxia inducible factor 1 (HIF1) and express hypoxia-regulated genes more robustly. This unusual metabolic situation clearly separates direct regulatory effects of redox balance from secondary effects of hypoxia per se. The physiological significance of the FAS pathway is thus the harnessing of its oxidizing power for improving redox balance despite conditions of more extreme hypoxia. Similar hypoxia defense strategies are found in animal species that are unusually tolerant to oxygen lack. Our hypothesis is that the metabolic organization in the "low zinc, low citrate" phenotype reflects an hypoxia-defense adaptation geared toward redox balance, with prostate cancer cells being relatively more oxidized, even if more hypoxic, than normal prostate cells. Recognition and understanding of these redox balancing and hypoxia defense functions may lead to new intervention strategies by developing new intracellular targets for prostate cancer therapy.
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PMID:Going malignant: the hypoxia-cancer connection in the prostate. 1221 May 36

Lysosomes, lysosomal enzymes and oxidant processes are known to be involved in cancer processes. The prostasomes contain proteins and enzymes that would constitute pathways for the hydrolysis of proteins and peptides. However, integrated biochemical and cell biology studies are necessary to understand how lysosomal enzymes and prostasomal enzymes combined with oxidant processes could initiate cancer. Most prostate cancer is likely to be initiated in the prostate duct system. The lysosomal enzymes acid phosphatase and glucosidase and prostasomal proteins and enzymes are found in human semen and therefore have come through prostate ducts. The hypothesis presented here is that the lysosomal enzymes and prostasomes are exocytosed from prostate cells into the duct system of the prostate where their hydrolytic enzymes and oxidative processes, for example, the iron from the iron-sulfur clusters of the prostasomal dehydrogenases, damage proteins and other components of cells leading to the initiation of cancer. Risk factors for prostate cancer are known to initiate activity of lysosomal enzymes and could initiate activity of prostasomal enzymes. These risk factors include: ionizing radiation, oxidative stress, environmental toxicants and dietary components including those with high fat content. Other dietary components in fruits and vegetables protect against prostate cancer and can be hypothesized as decreasing cellular output of lysosomal or protasomal enzymes or inhibiting lysosomal and prostasomal enzymes in the duct system. Measurements of multiple lysosomal and prostasomal enzyme activities and their biochemical pathways are vital to the understanding of protectors to inhibit lysosomal or prostasomal enzyme activities that might be leading to prostate cancer. Inhibitors of lysosomal and prostasomal enzymes can be investigated in cellular and biochemical systems, and these inhibitors could be used to control these enzyme activities in vivo. In situ enzyme analyses including substrates producing fluorescent products are applicable. Screening assays could be developed to detect in vivo lysosomal and prostasomal enzyme activities in semen. Lysosomal enzyme activities may be precursors to the onset of other kinds of cancer with other similar non-invasive screening techniques possible. Present knowledge encompasses mobilization of sperm when prostasomes bind to sperm in semen. A further hypothesis of this study projects that prostasomal dehydrogenases and their NADH products initiate the formation of ATP in the sperm mitochondria which activates flagellar movement. This overall hypothesis suggests protection against prostate cancer by inhibitors of lipid peroxidation including the dietary antioxidants selenium, vitamin E and lycopene and also cysteine glutathione.
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PMID:Lysosomal and prostasomal hydrolytic enzymes and redox processes and initiation of prostate cancer. 1582 10

Most malignant cells are highly glycolytic and produce high levels of reactive oxygen species (ROS) compared to normal cells. Mitochondrial glycerophosphate dehydrogenase (mGPDH) participates in the reoxidation of cytosolic NADH by delivering reducing equivalents from this molecule into the electron transport chain, thus sustaining glycolysis. Here, we investigate the role of mGPDH in maintaining an increased rate of glycolysis and evaluate glycerophosphate-dependent ROS production in prostate cancer cell lines (LNCaP, DU145, PC3, and CL1). Immunoblot, polarographic, and spectrophotometric analyses revealed that mGPDH abundance and activity was significantly elevated in prostate cancer cell lines when compared to the normal prostate epithelial cell line PNT1A. Furthermore, both the glycolytic capacity and glycerophosphate-dependent ROS production was increased 1.68- to 4.44-fold and 5- to 7-fold, respectively, in prostate cancer cell lines when compared to PNT1A cells. Overall, these data demonstrate that mGPDH is involved in maintaining a high rate of glycolysis and is an important site of electron leakage leading to ROS production in prostate cancer cells.
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PMID:High activity of mitochondrial glycerophosphate dehydrogenase and glycerophosphate-dependent ROS production in prostate cancer cell lines. 1596 8

We examined the impact of EGFR-ERK signaling on poly (ADP-ribose) polymerase (PARP) activation following ionizing irradiation of human prostate cancer (PCa) cell lines displaying marked differences in ERK dependence. PARP activation was indicated by the appearance of polyADP-ribose, the incorporation of P32-labelled NADH, and by cellular NADH. EGFR-ERK signaling was manipulated through ligand activation or signal interruption using the tyrphostin AG1478, or MEK inhibitor PD 184352. EGF activation of ERK prior to irradiation was associated with a marked increase in PARP activation and decreased survival in both cell lines. Prior inactivation of PARP protected both cell lines from the initial decrease in NAD+ and improved the survival of LNCaP cells following combined EGF and IR treatment. MEK inhibitor PD 184352 also reduced PARP activation and improved LNCaP survival following EGF and IR treatment. These data imply that PARP activation following exposure to ionizing radiation is enhanced through EGFR-ERK signaling.
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PMID:Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. 1729 9


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