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At least 613 records · Page 34Linked to original sources
PubMed2000

Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells.

Interleukin 6 (IL-6) is a cytokine that regulates not only immune and inflammatory responses but also the growth of some tumors, including prostate carcinomas. IL-6 signals through Janus kinase, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase and is also able to induce androgen receptor (AR)-mediated gene activation in prostate cancer, which is an important process in prostate cancer androgen-independent progression. We now show that IL-6-induced AR-mediated gene activation requires the activation of STAT3 by IL-6 in LNCaP prostate cancer cells. In particular, STAT3 associates with AR in an androgen-independent but IL-6-dependent manner. Inhibition of STAT3 rather than mitogen-activated protein kinase results in inhibition of AR-mediated gene activation in response to IL-6. These findings not only identify STAT3 as an important signaling molecule required for IL-6-signaling to induce AR-mediated gene activation in prostate carcinoma cells but also reveal the importance of activated STAT3 in human tumor development and progression.

Carrier Proteins↗
PubMed2000

Peroxisome proliferator-activated receptor alpha is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma.

Peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARalpha is activated by peroxisome proliferators and fatty acids and has been shown to be involved in the transcriptional regulation of genes involved in fatty acid metabolism. In rodents, the PPARalpha-mediated change in such genes results in peroxisome proliferation and can lead to the induction of hepatocarcinogenesis. Using the mRNA differential display technique and Northern blot analysis, we have shown that chronic exposure of the prostate cancer epithelial cell line LNCaP to the synthetic androgen mibolerone results in the down-regulation of PPARalpha mRNA. Levels of PPARalpha mRNA are reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h. PPARalpha-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPARalpha-activating ligand Wy-14,643 in LNCaP cells. In situ hybridization and immunohistochemical analyses showed that PPARalpha expression in prostate is confined to epithelial cells. In benign prostatic tissue, PPARalpha mRNA was either absent or only weakly expressed in the basal epithelial cells. In 11 of 18 (61%) poorly differentiated (Gleason score, 8-10) prostatic carcinoma specimens, there was strong expression of PPARalpha compared with 4 of 12 Gleason score 7 tumors and 2 of 11 Gleason score 3-6 tumors (P < 0.01). These results suggest that PPARalpha is found and functional in human prostate and is down-regulated by androgens. The role of PPARalpha may be to integrate dietary fatty acid and steroid hormone signaling pathways, and its overexpression in advanced prostate cancer may indicate a role in tumor progression with the potential involvement of dietary factors.

Adenocarcinoma↗
PubMed2000

Reversible effect of testosterone undecanoate injection on spermatogenesis in rats.

AIM: To study the effect of testosterone undecanoate (TU) injection on spermatogenesis in rats. METHODS: Twenty adult SD rats received vehicle or TU (8 mg/kg, 19 mg/kg or 625 mg/kg) injection, im, every 15 days for 60 days, and another 38 animals received similar treatments for 130 days with half of them undergoing a recovery phase of 120 days (5 rats for each treatment). At the end of the treatment, testes were removed and the diameter of the seminiferous tubules and the number of late elongated spermatids (steps 15-19) per testis were estimated with stereological methods as a measure of the spermatogenic efficiency. RESULTS: Low dose (8 mg/kg) TU treatment virtually had no effect on spermatogenesis. A dose of 19 mg/kg slightly suppressed spermatogenesis 60 days after treatment, and severe suppression occurred after another 70 days of dosing. Spermatogenesis was completely recovered at the end of the recovery phase. Large dose (625 mg/kg) TU treatment did not significantly affect spermatogenesis and was well tolerated by animals. CONCLUSION: TU injection reversibly suppresses spermatogenesis in rats.

Animals↗
PubMed2001

[De La Chapelle syndrome].

OBJECTIVE: The De La Chapelle syndrome (XX male) is a peripheral hypogonadism concerning males with 46,XX karyotype. We conducted a retrospective study of 18 cases and report the main clinical biological and hormonal characteristics. PATIENTS AND METHODS: Clinical features (weight, height, aspect of the external genital organs, body hair, gynecomastia), hormone levels (testosterone, gonadotrophin, baseline and stimulated prolactin estradiol), and results of a Barr test and karyotype were recorded in all patients in addition to search for the SRY gene (in 8 of the 18 patients). Findings were compared with a matched male population and a Klinefelter syndrome population. RESULTS: Microrchidia was found in almost all the patients while the penis had a normal size. Signs of hypoandrogenism were frequent and gynecomastia was present in half the cases. De La Chapelle patients differed from Klinefelter patients by the absence of dysmorphism. DISCUSSION: Patients with De La Chapelle syndrome diagnosed around the age of 20 years do not have borderline disorders associating genitalia anomalies or sexual ambiguity. The majority of the patients bear the testis determining SRY gene on one of the X chromosomes, providing the rational explanation of the male phenotype, but 20% of the XX males doe not have this gene. The role of certain key genes that could be implicated in abnormal sexual differentiation is known, but the complexity and heterogeneous nature of this syndrome leaves many questions unanswered. Therapy is based on androgen replacement therapy given at an early stage.

Administration, Oral↗
PubMedDate not supplied

Transcriptional regulation of the androgen signaling pathway by the Wilms' tumor suppressor gene WT1.

The androgen-signaling pathway plays a critical role in prostate cancer development and progression. We have recently demonstrated that the Wilms' tumor suppressor gene product, WT1, binds to multiple sites in the androgen receptor (AR) promoter and transcriptionally represses the AR gene promoter in vitro. We asked whether WT1 repression of the endogenous AR gene interferes in the androgen signal transduction cascade and modifies AR target gene expression. We analyzed the effect of WT1 (-/-) overexpression on an AR target gene reporter construct that contains the luciferase gene, the ElB TATA box, and two copies of the androgen-response element (ARE), the dimeric AR binding site. Luciferase activity was determined in 293 kidney and TM4 Sertoli cells, two nontumorigenic cell lines that express both AR and WT1. Cells were cotransfected by lipofectamine in the presence or absence of the synthetic androgen R1881. Results showed that overexpression of WT1 downregulates ARE-reporter gene transcription in both cell lines tested. The inhibitory effect of WT1 on the AR target gene construct was dose-dependent and androgen-independent in 293 cells, whereas in TM4 cells it was androgen-dependent. Additionally, a zinc-finger mutant WT1 (-/-) expression construct, R394W, failed to decrease luciferase activity, suggesting that WT1 downregulates the ARE-reporter gene construct activity by directly repressing the endogenous AR gene promoter. Furthermore, we analyzed the expression of WT1 and AR mRNA in several prostate cancer cell lines in order to understand the role WT1 may play in prostate cancer development and progression. Gel analysis of cDNA amplified by RT-PCR of AR and WT1 RNA from prostate cancer and non-prostatic cell lines showed that LNCaP and MDAPCa2b, two metastatic prostate cancer cell lines which are androgen-sensitive, expressed AR but not WT1. Du145 and PC3, two cell lines from advanced metastatic prostate cancer, which are characterized as androgen-independent and -insensitive, did not express AR but expressed a high level of WT1. Two non-prostatic cell lines, T47D and 293, weakly co-expressed AR and WT1. This inverse relationship between AR and WT1 expression in prostate cancer cell lines, together with WT1 repression of the AR promoter, suggest a role for WT1 in the androgen signaling pathway and in prostate cancer development and progression.

Androgens↗
PubMed2001

Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen.

The androgen receptor (AR) is highly expressed in androgen-dependent and recurrent prostate cancer (CaP) suggesting it has a role in the growth and progression of CaP. Previously proposed mechanisms for AR reactivation in recurrent CaP include altered growth factor signaling leading to protein phosphorylation and AR mutations that broaden ligand specificity. To further establish a role for AR in recurrent CaP, we compared several properties of AR in relation to the growth response to low levels of androgens in model systems of androgen-dependent and recurrent CaP. AR from all of the tumors and cell lines bound [3H]R1881 with similar high affinity (mean Kd, 0.12 nM). In the absence of androgen, AR in androgen-dependent LNCaP cells was unstable with a degradation half-time (t(1/2)) of 3 h at 37 degrees C. In contrast, AR was 2-4 times more stable in recurrent CWR22 tumors (t(1/2), >12 h) and CWR-R1 or LNCaP-C4-2 cell lines (t(1/2), 6-7 h) derived from recurrent prostate tumors. In the recurrent CWR22 tumor and its CWR-R1 cell line grown in the absence of androgen, AR immunostaining was entirely nuclear, whereas under the same conditions AR in LNCaP-C4-2 and LNCaP cells was predominantly nuclear but was also detected in the cytoplasm. High level expression, increased stability, and nuclear localization of AR in recurrent tumor cells were associated with an increased sensitivity to the growth-promoting effects of dihydrotestosterone in the femtomolar range. The concentration of dihydrotestosterone required for growth stimulation in CWR-R1 and LNCaP-C4-2 cells was four orders of magnitude lower than that required for androgen-dependent LNCaP cells. The results suggest that AR is transcriptionally active in recurrent CaP and can increase cell proliferation at the low circulating levels of androgen reported in castrated men.

Androgens↗
PubMed2001

Description and evaluation of a short-term reproduction test with the fathead minnow (Pimephales promelas).

Due to the time and expense associated with full life-cycle testing, most current toxicity tests with fish do not explicitly consider reproductive output as an endpoint but, rather, focus on early life-stage survival and development. However, some classes of chemicals could adversely impact reproduction at concentrations below those that affect development. Further, estimates of the effects of toxic compounds on reproductive output can be critical to the ecological risk assessment process. In this manuscript, we describe a short-term reproduction test with the fathead minnow (Pimephales promelas) and evaluate the test using two model reproductive toxicants, methoxychlor (an estrogenic compound) and methyltestosterone (an androgenic chemical). The test is initiated with reproductively mature animals and is comprised of a pre-exposure phase of 14 to 21 d, followed by a chemical exposure of up to 21 d. During and at completion of the test, several endpoints related to reproductive fitness and endocrine function are assessed. Both chemicals evaluated in our study caused a significant decrease in fecundity of the fish at nominal concentrations of 5.0 micrograms/L (methoxychlor) and 0.2 mg/L (methyltestosterone). Methoxychlor decreased plasma concentrations of one or more steroids (testosterone, 11-ketotestosterone, beta-estradiol) in both sexes and caused a significant induction of plasma vitellogenin in males, a response consistent with activation of the estrogen receptor by the pesticide (or its metabolites). Methyltestosterone decreased plasma concentrations of sex steroids and adversely affected gonadal status (as evaluated by relative weight and histopathology) in both sexes. The androgenic nature of methyltestosterone was clearly expressed as masculinization of exposed females via formation of nuptial tubercles, structures normally present only in reproductively active males. The chemical also caused a significant induction of plasma vitellogenin in both males and females; this unexpected estrogenic response was most likely due to aromatization of the androgen to a form capable of binding to the estrogen receptor. These studies demonstrate the utility of this short-term assay for identifying chemicals that exert reproductive toxicity through alterations in endocrine systems controlled by estrogens and androgens.

Animals↗
PubMed2001

Androgen blocks apoptosis of hormone-dependent prostate cancer cells.

Androgen plays a critical role in the promotion and growth of prostate cancer. Androgen ablation has an expanding role in prostate cancer treatment and is now used to improve the efficacy of radiation therapy in addition to its role in treatment of metastatic disease. Here we show that androgen interferes with induction of prostate cancer cell death induced by a variety of stimuli. The effect of androgen on cell death occurs predominantly by interference with caspase activation and the inhibition of caspase cleavage in both the extrinsic and intrinsic cell death pathways. Androgen inhibited apoptosis induced by both tumor necrosis factor alpha (TNF-alpha) and by Fas activation with or without concomitant irradiation. An antiapoptotic effect was seen in the presence of R1881, dihydrotestosterone, and also 17beta-estradiol within 24 h of death induction. Sustained inhibition of apoptosis at 72 h was seen only with R1881, dihydrotestosterone, cyproterone acetate, and hydroxyflutamide. Androgen treatment inhibited activation of caspases-8, -7, and -9 by TNF-alpha +/- irradiation. Androgen attenuated BAX expression and blocked appearance of the proapoptotic p18 fragment of BAX. Androgen also abrogated BID cleavage induced by TNF-alpha + irradiation that contributed to a decrease in cytochrome c egress from mitochondria induced by TNF-alpha +/- irradiation. There was also decreased mitochondrial depolarization in response to TNF-alpha + irradiation. Production of the proapoptotic lipid metabolite ceramide was not affected by androgen, but androgen acted downstream from ceramide generation because R1881 blocked cell-death induction by bacterial sphingomyelinase. Inhibition of phosphoinositol-3-kinase activity by wortmannin induced apoptosis that was also blocked by androgen, but there was no effect on protein levels or phosphorylation of AKT, indicating that R1881 did not interact with survival signaling of phosphoinositol-3-kinase. Lastly, androgen inhibited activation of nuclear factor-kappaB during death induction, but the effect of androgen on cell death was not mediated by interference with the nuclear factor-kappaB pathway. The data suggest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli.

Androgens↗
PubMed2001

Androgen receptor mediates the reduced tumor growth, enhanced androgen responsiveness, and selected target gene transactivation in a human prostate cancer cell line.

The growth and development of the prostate gland are regulated by the androgen and the androgen receptor (AR). Despite our molecular understanding of the roles of the AR regulating; a downstream target gene transcription, the direct or indirect (stromally mediated) actions of the androgen in controlling prostate cell growth and differentiation are still unclear. In this report, an invasive; and metastatic human prostate tumor cell line, androgen-repressed human prostate cancer cell line (ARCaP), either transduced with wild-type human AR (hAR) or a control neomycin-resistant plasmid DNA, was used to evaluate the direct role of AR in regulating prostate tumor cell growth and gene transcription. Results showed that: (a) introduction of wild-type hAR to ARCaP cells restored positive androgen regulation of prostate tumor cell growth in vitro through an enhanced cell-cycle progression from G(0)/G(1) to S and G(2)-M phases; (b) hAR was shown to transactivate glucocorticoid-responsive element but not prostate-specific antigen promoter-directed reporter gene expression; and (c) hAR-transduced ARCaP cells exhibited reduced growth, invasion, and migratory behavior in vitro and tumor growth in vivo. These results suggest that the introduction of hAR into the invasive human prostate cancer ARCaP cell line restored its androgen-regulated cell growth, decreased the rate of tumor growth, and selectively activated AR target gene expression. These cellular functions in response to androgen are commonly associated with increased differentiation of prostate epithelial cells.

Androgens↗
PubMed2001

[Androgen therapy from the viewpoint of the internal medicine physician].

The partial androgen deficit of the ageing male is an essential part of the age-related changes of the endocrine system. Clinically relevant disturbances (co-) caused by a relative testosterone-deficit are: changes of body composition (increase of fat mass, decrease of lean tissue mass), decrease of muscle strength and mass, changes of the lipid profile, cardiovascular disease, osteoporosis and anemia. Controlled studies revealed a positive effect of testosterone substitution on body composition, muscle strength, bone metabolism and erythropoesis. Moreover, a protective effect on the development of coronary artery disease could be demonstrated by an improvement of the lipid profile, decrease of obesity and insulin resistance and by a direct effect on the coronary vessels. Clinically evident hypogonadism is a clear indication for testosterone-substitution also in the ageing male, whereas in the case of the partial testosterone-deficit in the absence of sufficient data at this time no general recommendation for substitution can be given; one has to decide about a (experimental) therapy in the individual patient. In every case the contraindications of a testosterone-supplementation (carcinoma of the prostate, elevated PSA-values, polyglobulia, sleep-apnea-syndrome) have to be observed, a continuous survey of the therapy, especially of the prostate is essential. A general recommendation for a substitution with dehydroepiandrosterone (DHEA) can not be given.

Adult↗