UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A review of findings is given which relate to the levels of circulating melatonin as well as the urinary excretion of its main peripheral metabolite 6-sulphatoxymelatonin (aMT6s) in patients with different types of cancer as well as in tumor-bearing animals. Clinical results show that circulating melatonin tends to be depressed in patients with primary tumors of different histological types including both endocrine-dependent (mammary, endometrial, prostate cancer) and endocrine-independent tumors (lung, gastric, colorectal cancer). Reduction of melatonin is most pronounced in patients with advanced localized primary tumors, such as mammary and prostate cancer where a clear negative correlation with tumor-size exists. The phenomenon of a reduction of circulating melatonin appears to be a transient one since patients with recidives show a normalization of melatonin. Surgical removal of the primary tumor does, however, not lead to normalization indicating that complex systemic changes appear to be involved in the down-regulation of melatonin. It is unclear at present, whether circulating melatonin is depleted in cancer patients due to a reduced production by the pineal gland or due to certain peripheral metabolic processes, although no evidence for an enhanced hepatic degradation to aMT6s, the main peripheral metabolite of melatonin, was found. The reduction of circulating melatonin is accompanied by neuroendocrine changes affecting the circadian secretion of the adenohypophyseal hormones prolactin, somatotropin and thyroid-stimulating hormone. In contrast to the above-described types of tumors many patients with ovarian cancer show highly elevated levels of melatonin perhaps due to the production of tissue-specific growth factors that could affect pineal melatonin secretion. Experiments with tumor-bearing animals clearly demonstrate that nocturnal circulating melatonin is modulated due to malignant growth. Detailed investigations with chemically induced mammary tumors in rats and serial transplants derived thereof show that slow-growing and well-differentiated tumors containing epithelial cell elements (adenocarcinomas and carcinosarcomas) lead to an enhanced production of melatonin involving activation of the rate-limiting enzyme of pineal melatonin biosynthesis (serotonin N-acetyltransferase) probably due to elevation of the sympathetic tone in response to a stimulation of the cellular immune system by malignant growth. As opposed to that nocturnal melatonin is depleted in animals with fast-growing mammary tumor transplants when myoepithelial-mesenchymal conversion leads to pure sarcomas. The reduction of melatonin appears to be due to either a reduced availability of the precursor amino acid tryptophan because of a glucocorticoid-induced activation of the hepatic enzyme tryptophan 2,3-dioxygenase or a direct peripheral degradation of melatonin via indoleamine 2,3-dioxygenase expressed in tumor and/or other tissues. The significance of these clinical and experimental findings relating to melatonin is discussed both in terms of their practical application as a possible tumor marker and from a theoretical point of view to understand better the mechanisms involved in complex host-tumor interactions involving the neuroimmunoendocrine network.
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PMID:Melatonin in cancer patients and in tumor-bearing animals. 1072 Oct 63

Histamine (H2) receptor antagonists, such as cimetidine and ranitidine, became available in the late 1970s and presently number among the most commonly used drugs. Cimetidine has been hypothesized to exert a cancer preventive effect on the prostate due to its ability to inhibit the binding of dihydrotestosterone to androgen receptors. Other hormonal effects of this drug include increases in serum prolactin levels and inhibition of 2-hydroxylation of estradiol. We assessed risk of prostate and breast cancers in a cohort of 48,512 members of the Group Health Cooperative of Puget Sound prescribed cimetidine or another H2 blocker between 1977 and 1995. Standardized incidence ratios were calculated comparing the observed numbers of cancers to those expected based on population rates in western Washington State. Because cimetidine, but not other H2 blockers, influences hormonal activity and metabolism, we conducted nested case-control studies comparing cancer risk among individuals treated with cimetidine to individuals who used other H2 blockers. Risks of breast and prostate cancers were identical among users of cimetidine and users of other H2 blockers (relative risk, 1.0 for both cancers). We observed no trend in risk of breast cancer according to time since first or last cimetidine prescription or number of cimetidine prescriptions filled. For prostate cancer, our findings were similar save for a modest increase in risk among men who had filled > or =21 cimetidine prescriptions (relative risk, 1.4; 95% confidence interval, 1.0-1.9). Our results suggest that use of cimetidine does not influence risk of female breast cancer. Further, these data provide little evidence to support the previously hypothesized preventive effect of cimetidine on risk of prostate cancer.
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PMID:Cimetidine use and risk of prostate and breast cancer. 1075 Jun 71

Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e. anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA), in the control of inflammation and of the proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2-AG can be induced by stimulation with either Ca(2+) ionophores, lipopolysaccharide, or platelet activating factor in macrophages, and by ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a widely used model for mast cells). These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate cytokine and/or arachidonate release from macrophages in vitro, regulate serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models of inflammatory pain. However, the involvement of endogenous CFADs and cannabinoid CB(1) and CB(2) receptors in these effects is still controversial. In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation. Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity. These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here.
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PMID:Cannabimimetic fatty acid derivatives in cancer and inflammation. 1078 41

Prolactin stimulates citrate accumulation in prostate cells by increasing the expression of mitochondrial aspartate aminotransferase (mAAT). In this study, we further investigated the mechanism of prolactin regulation of mAAT expression in rat lateral prostate and LNCaP and PC-3 prostate cancer cells. Prolactin and 12-O-tetra-decanoylphorbol 13-acetate (TPA) increased the mAAT mRNA level twofold to fourfold. In addition, prolactin and TPA increased protein kinase C (PKC) activity in prostate cells 20% to 60% and 40% to 210%, respectively. The effects of both prolactin and TPA on mAAT mRNA were eliminated by downregulation of PKC. The effect of prolactin and TPA on gene transcription was determined using mAAT-chloramphenicol acetyltransferase (CAT) reporter-gene constructs, transiently transfected into PC-3 cells. The 59 untranslated region of the precursor form (pmAAT) of the mAAT gene contains five sequences that are homologous to the consensus TPA response elements (TRE). Reporter constructs with various combinations of these sequences were used to assay prolactin stimulation of CAT transcription in PC-3 cells. Prolactin increased CAT expression in PC-3 cells transfected with a reporter gene containing four of the TRE consensus sequences. Another CAT reporter gene, which contained two of the putative TREs, was also stimulated by prolactin, but a third reporter, containing the two other TRE sequences, was not induced by prolactin. These results suggest that prolactin regulates mAAT at the transcriptional level. Moreover, because both prolactin and TPA induced PKC activity, and because the effects of prolactin and TPA were eliminated when PKC was downregulated, we postulate that the prolactin effect on mAAT expression is mediated via the diacylglycerol PKC signal transduction pathway in rat lateral prostate and human prostate cancer cells.
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PMID:Protein Kinase C Mediates Prolactin Regulation of Mitochondrial Aspartate Aminotransferase Gene Expression in Prostate Cells. 1085 Dec 92

The effects of the polypeptide hormone prolactin (PRL) in the development and regulation of benign prostate hyperplasia (BPH) and also in prostate cancer are not very well characterized. This study examines the action of PRL, either alone or in association with androgens [testosterone (T) or dihydrotestosterone (DHT)], in the rat prostate gland. The effects of PRL and androgens were investigated after 30 and 60 days in control, castrated, castrated with a substitutive implant of T or DHT, and sham-operated Wistar rats. To enhance PRL release, we induced hyperprolactinemia by administering chronic injections of sulpiride (40 mg. kg(-1). day(-1)). Chronic hyperprolactinemia induces enlargement and inflammation of the lateral rat prostate without any histological changes on ventral and dorsal lobes. We also demonstrate that hyperprolactinemia induces Bcl-2 overexpression in the lateral rat prostate and that this could inhibit the level of apoptosis. The in vivo model established here is a useful in vivo approach for studying the hormonal regulation of normal and pathological prostate development.
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PMID:Effects of hyperprolactinemia on rat prostate growth: evidence of androgeno-dependence. 1112 Jun 66

Prolactin, a pituitary peptide hormone with multiple effects, stimulates prostate growth in experimental models. In humans, prolactin receptors are present in the prostate and are particularly abundant in pre-cancerous lesions. This suggests that prolactin could also be involved in the development of prostate cancer. In this study, we tested the hypothesis that elevated levels of circulating prolactin are associated with an increase in prostate cancer risk. We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort using plasma samples collected from 29,560 men at a health survey. We measured prolactin in plasma from 144 men who had a diagnosis of prostate cancer after a median follow-up time of 4 years after health survey and from 289 controls matched for age and date of recruitment. Risk was not associated with plasma prolactin levels in univariate regression analysis. Odds ratios of prostate cancer for increasing quartiles of prolactin were 1.0, 0.92 (95% CI 0.51-1.65), 0.82 (0.45-1.51) and 0.85 (0.49-1.47). Relative risk estimates remained unchanged after adjustments for height and weight or for plasma levels of testosterone, sex hormone-binding globulin, IGF-I and IGF-binding protein-3. Elevated circulating levels of prolactin were not related to an increase in prostate cancer risk, indicating that high circulating prolactin is not associated with development of prostate cancer.
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PMID:Plasma prolactin and prostate cancer risk: A prospective study. 1129 Oct 87

Testosterone was reported to affect a variety of reproductive endpoints. More notable were the effects of dihydrotestosterone on cell proliferation in the prostate cancer cell model LNCaP and Sertoli cell function. Testosterone production was also biphasically affected by prolactin that was administered to adult testicular cells in vitro.
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PMID:Androgens: biphasic dose responses. 1150 78

Others have demonstrated the presence of an autocrine prolactin (PRL) growth loop in the normal human prostate. In this study we have used three human prostate cancer cell lines but have focused on the androgen-independent human prostate cancer cell line, DU145, to ask: (a) whether this autocrine growth loop is maintained beyond the loss of androgen sensitivity in the progression of prostate cancer; and (b) whether interruption of this growth loop by a PRL receptor antagonist, an S179D mutant PRL, could inhibit the formation of DU145-derived tumors. The autocrine loop was examined in most detail in the DU145 cell line but was demonstrated to be functional in all three of the lines by the reversible inhibition of growth in vitro by the S179D PRL receptor antagonist. To investigate the effect of S179D PRL on the growth of DU145 tumors in nude mice two sets of experiments were performed. In the first set, Alzet minipumps containing no PRL, wild-type (WT) PRL, or the S179D PRL (the last two delivering 4.56 microg/24 h and 4.26 microg/24 h, respectively), were implanted s.c. on day 1. On day 4, 5 x 10(6) DU145 cells were injected s.c. in the hindquarter. On day 22, the animals were killed, tumors were removed, measured, and subsequently fixed and processed for histological confirmation of tumor formation. The incidence of tumors in the no-PRL control group was 9/11 animals (82%). In the animals treated with WT PRL, the incidence was 8/10 (80%), whereas in the animals treated with the S179D PRL, the incidence was markedly reduced to 3/11 (27%). Although WT PRL had no effect on the incidence of tumors, the average size of the tumors increased from 25.8 +/- 5.99 mm(3) in controls to 66.66 +/- 18.06 mm(3) in WT PRL-treated animals. In the second set of experiments, 5 x 10(6) DU145 cells were injected on day 1. On day 18, Alzet minipumps containing no PRL, WT PRL, or S179D PRL were implanted. On day 42, the animals were killed and the tumors processed as before. S179D PRL caused a reduction in tumor size from 1731 +/- 283 mm(3) in the no-PRL controls to 1031 +/- 295 mm(3), whereas WT PRL slightly increased the size to 2118 +/- 630 mm(3). We conclude that PRL is used as an autocrine growth factor by human prostate cancer cells both in vitro and in vivo and that interruption of this growth loop in vivo inhibits tumor initiation and the growth of well-established tumors.
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PMID:A molecular mimic of phosphorylated prolactin markedly reduced tumor incidence and size when DU145 human prostate cancer cells were grown in nude mice. 1150 59

Human prolactin (hPRL) has been reported to be involved in breast and prostate cancer development. The hPRL receptor (hPRLR) is expressed in a wide variety of tissues in at least three isoforms. In this study, a one-step real time reverse transcription PCR technique was used to determine relative expression levels of hPRLR mRNA in eleven human breast cancer cell lines, HeLa cells, three prostate cancer cell lines and nine normal human tissues. The housekeeping gene beta-actin was used for internal normalization. We demonstrate that hPRLR mRNA is up-regulated in six of the eleven breast cancer cell lines tested when compared with normal breast tissue. Of the cancer cell lines tested, we found that T-47D cells have the highest level of hPRLR mRNA, followed by MDA-MB-134, BT-483, BT-474, MCF-7 and MDA-MB-453 cells. In two breast cancer cell lines (MDA-MB-468 and BT-549), the hPRLR levels were found to be comparable to that of normal breast tissue. Three breast cancer cell lines (MDA-MB-436, MDA-MB-157 and MDA-MB-231) expressed hPRLR mRNA at levels lower than that of normal tissue. In contrast, in all three commonly used prostate cancer cell lines (LNCaP, PC-3 and DU 145), the levels of hPRLR mRNA were found to be down-regulated relative to that of normal prostate tissue. Of nine normal human tissues tested, we found that the uterus and the breast have the highest levels of hPRLR mRNA, followed by the kidney, the liver, the prostate and the ovary. The levels of hPRLR mRNA were the lowest among the trachea, the brain and the lung.
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PMID:Quantification of prolactin receptor mRNA in multiple human tissues and cancer cell lines by real time RT-PCR. 1157 5

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.
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PMID:Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. 1219 95

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