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

Antioxidants, such as vitamin E, are being investigated for efficacy in prostate cancer prevention. In this study, we show that the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), has antiandrogen activity in prostate carcinoma cells. In the presence of PMCol, the androgen-stimulated biphasic growth curve of LNCaP human prostate carcinoma cells was shifted to the right. The PMCol-induced growth shift was similar to that produced by treatment with the pure antiandrogen bicalutamide (i.e., Casodex), indicative of androgen receptor (AR) antagonist activity. The concentration of PMCol used was below the concentration required to affect cell growth or viability in the absence of androgen. Using an AR binding competition assay, PMCol was found to be a potent antiandrogen in both LNCaP and LAPC4 cells, with an IC(50) of approximately 10 micro M against 1 nM R1881 (methyltrienolone; a stable, synthetic androgen). Prostate-specific antigen release from LNCaP cells produced by androgen exposure with either 0.05 or 1.0 nM R1881 was inhibited 100% and 80%, respectively, by 30 micro M PMCol. Also, PMCol inhibited androgen-induced promoter activation in both LNCaP and LAPC4 cells. However, PMCol did not affect AR protein levels, suggesting that the inhibitory effects of PMCol on androgenic pathways were not due to decreased expression of the AR. Therefore, growth modulation by the antioxidant moiety of vitamin E in androgen-sensitive prostate carcinoma cells is due, at least in part, to its potent antiandrogenic activity.
 ...
PMID:Androgen antagonist activity by the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol in human prostate carcinoma cells. 1293 70

The androgen-androgen receptor (AR) signaling pathway plays a key role in proper development and function of male reproductive organs, such as prostate and epididymis, as well as nonreproductive organs, such as muscle, hair follicles, and brain. Abnormalities in the androgen-AR signaling pathway have been linked to diseases, such as male infertility, Kennedy's disease, and prostate cancer. Regulation of AR activity can be achieved in several different ways: modulation of AR gene expression, androgen binding to AR, AR nuclear translocation, AR protein stability, and AR trans-activation. This review covers mechanisms implicated in the control of AR protein expression and degradation, and their potential linkage to the androgen-related diseases. A better understanding of such mechanisms may help us to design more effective androgens and antiandrogens to battle androgen-related diseases.
 ...
PMID:Endocrine mechanisms of disease: Expression and degradation of androgen receptor: mechanism and clinical implication. 1297 Feb 60

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway controls several important biological functions, such as cell growth regulation, apoptosis, and migration. However, the way in which PI3K/Akt controls androgen receptor (AR)-mediated prostate cancer cell growth remains unclear and controversial. Here, we demonstrate that the PI3K/Akt pathway regulates AR activity in a cell passage number-dependent manner. Specifically, PI3K/Akt pathway can suppress AR activity in androgen-dependent LNCaP cells with low passage numbers. In contrast, it can also enhance AR activity in LNCaP cells with high passage numbers. Furthermore, we also demonstrate that insulin-like growth factor-1 can activate the PI3K/Akt pathway that results in the phosphorylation of AR at Ser210 and Ser790. The consequence of these events may then change the stability of AR protein. Together, our results demonstrate that the PI3K/Akt pathway may have distinct mechanisms to modulate AR functions in various stages of prostate cancer cells and that a combined therapy of antiandrogens and anti-PI3K/Akt inhibitors may be worth considering as a future therapeutic approach to battle prostate cancer.
 ...
PMID:Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. 1455 44

In recent studies, we found that sulindac sulfide (SS), exisulind, CP248, and CP461 induce growth inhibition and apoptosis in a series of human prostate cancer cell lines, irrespective of cyclooxygenase expression, p53 mutations, or bcl-2 overexpression. Exisulind also inhibited the growth of the androgen-dependent LNCaP human prostate cancer cell line when grown as a xenograft in nude mice. This study demonstrates that doses of these compounds that induce growth inhibition and apoptosis in LNCaP cells also cause decreased prostate-specific antigen (PSA) secretion and decreased cellular levels of PSA. These effects appear to be a result, at least in part, of inhibition of the androgen receptor (AR) signaling pathway because the treated cells also display decreases in the level of the AR protein and mRNA and inhibition of transcription of an AR promoter luciferase reporter in transient transfection assays. SS and exisulind were more effective in inhibiting the expression of PSA and the AR than CP248 or CP461, apparently because of differential effects of these compounds on specific transcription factors. These findings suggest that the growth inhibition by these compounds in human prostate cancer cells may be mediated, in part, by inhibition of AR signaling. Thus, these compounds may provide a novel approach to the prevention and treatment of human prostate cancer.
 ...
PMID:Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells. 1458 72

A subject of current interest, especially in the development of androgen refractory prostate cancer, is the androgen receptor (AR) activation by growth factor receptors. Here, we report our work on the measurement of AR mRNA and protein expression in benign prostatic hyperplasia (BPH) and prostatic carcinoma (PCA) and evaluation of the relationship between AR, erbB-1 and erbB-2 gene expression determined in the same tissue. In order to define AR, erbB-1 and erbB-2 in human prostate neoplasms 36 benign prostatic hyperplasia, 46 prostatic carcinoma and 12 normal prostate gland samples were analysed. According to distant metastasis PCA tissues were divided into two categories: i) T1-4N0-3M0 (25 samples) and ii) T4N2-3M1 (21 samples). AR, erbB-1 and erbB-2 mRNA expression was estimated by RT-PCR. AR protein expression, both in nuclear and cytoplasmic fractions, was measured by Western blot technique. The association of AR mRNA and protein expression with erbB-1 and erbB-2 gene expression was evaluated. It was found that in clinically invasive (group II of PCA) prostate cancer cases AR mRNA expression was significantly correlated with erbB-2 mRNA expression (Spearman R coefficient 0.86, p<0.05). Interestingly, AR protein expression in this group of PCA was determined mainly in nuclear fraction. By Western blot AR protein was identified in 76.0% (16/21) and 23.8% (5/21) of PCA group II nuclear and cytoplasmic fractions, respectively. Furthermore, the mean AR protein level in nuclear fraction of clinically invasive (group II) PCA (0.82+/-0.04) was significantly higher (p<0.05) as compared to the normal group (0.56+/-0.11). In the case of T4N2-3M1 samples, significant correlation between AR protein level in nuclear fraction and erbB-2 mRNA expression (Spearman R coefficient 0.53, p<0.05) was stated.
 ...
PMID:Androgen receptor versus erbB-1 and erbB-2 expression in human prostate neoplasms. 1465 29

LNCaP prostate cancer cells express the aryl hydrocarbon receptor (AhR), and treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and an Ah-responsive reporter gene. Similar results were obtained with the selective AhR modulator 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF); however, TCDD but not 6-MCDF induced degradation of the AhR protein. TCDD and 6-MCDF inhibited growth of LNCaP cells, and inhibitory AhR-androgen receptor (AR) crosstalk was investigated in cells transfected with constructs containing the androgen-responsive probasin promoter (-288 to +28) (pPB) or three copies of the -244 to -96 region of this promoter (pARR(3)). Ten nanomolar dihydrotestosterone (DHT) and 17 beta-estradiol (E2) induced transactivation in LNCaP cells transfected with pPB or pARR(3); however, inhibitory AhR-AR crosstalk was observed only with the latter construct. 6-MCDF and TCDD did not inhibit DHT- or E2-induced transactivation in ZR-75 human breast cancer cells, indicating that these interactions were promoter and cell context-dependent. Both E2 and DHT stabilized AR protein in LNCaP cells; however, cotreatment with TCDD or 6-MCDF decreased AR protein levels. These results indicate that inhibitory AhR-AR crosstalk in prostate cancer cells is complex and for some responses, AR protein stability may play a role.
 ...
PMID:Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation. 1502 81

Androgens (testosterone), acting via the androgen receptor (AR) a nuclear transcription factor, regulate male sexual development and body composition. In addition, AR expression plays an important role in the proliferation of human prostate cancer and confers a better prognosis in breast cancer. AR mRNA stability is central to the regulation of AR expression in prostate and breast cancer cells, and recent studies have demonstrated binding by members of the ELAV/Hu and poly(C) RNA-binding protein families to a highly conserved UC-rich element in the 3'-untranslated region of AR mRNA, with functional impact on AR protein expression. Remarkably, a CAG trinucleotide repeat in exon 1 of the AR, the length of which has been linked to prostate cancer survival, is also a target for multiple RNA-binding proteins from a variety of human and murine tissues. In this review, we will detail the current knowledge of the mechanisms involved in regulating AR mRNA stability, the nature, potential role and structural biology of several novel AR mRNA-protein interactions, and the implications for novel therapeutics in human prostate cancer.
 ...
PMID:The androgen receptor mRNA. 1517 Aug 65

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M(r) of 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.
 ...
PMID:Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells. 1519 5

Defects in the PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor gene have been found in many human cancers including breast and prostate. Here we show that PTEN suppresses androgen receptor (AR) activity via a phosphatidylinositol-3-OH kinase/Akt-independent pathway in the early passage numbers prostate cancer LNCaP cells. We provide the direct links between PTEN and androgen/AR signaling by demonstrating that AR directly interacts with PTEN. The interaction between PTEN and AR inhibits the AR nuclear translocation and promotes the AR protein degradation that result in the suppression of AR transactivation and induction of apoptosis. The minimum interaction peptide within AR (amino acids 483-651) disrupts the interaction of PTEN with AR and reduces the PTEN effect on AR transactivation and apoptosis. Genetic approaches using PTEN-null mouse embryonic fibroblasts (MEFs) further demonstrate that both AR expression and AR activity were much higher in PTEN-null MEFs than wild-type MEFs, and reintroducing PTEN into PTEN-null MEFs dramatically reduced AR protein levels and AR activity. Interestingly, we also found that PTEN could suppress AR activity via the phosphatidylinositol-3-OH kinase/Akt-dependent pathway in the higher passage number LNCaP cells, because restoration of Akt activity blocks the effect of PTEN on AR activity. Together, these contrasting PTEN effects on AR activity in the same prostate cancer cell line with different passage numbers suggest that PTEN, via distinct mechanisms, differentially regulates AR in various stages of prostate cancers.
 ...
PMID:Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells. 1520 73

Androgens are critical in the development and maintenance of the male reproductive system and important in the progression of prostate cancer. The effects of androgens are mediated by the androgen receptor (AR), which is a ligand-modulated transcription factor that belongs to the nuclear receptor superfamily. We and others have previously shown that CREB-binding protein (CBP) can function as a coactivator for AR. Similar to some other nuclear receptor coactivators and/or the proteins that they interact with, CBP has histone acetyl transferase (HAT) activity that is thought to contribute to transcriptional activation by nuclear receptors. We have therefore assessed whether an increase in the histone acetylation status in the cell can influence AR transcriptional activity, by using the histone deacetylase (HDAC) inhibitors (HDACIs) trichostatin A (TSA), sodium butyrate (Na-But) and depsipeptide (FR901228). We found that inhibition of HDAC activity significantly increased the ability of endogenous AR in LNCaP cells, or ectopically expressed AR in HeLa cells, to activate transcription from AR-dependent reporter constructs. In addition, HDACIs increased the androgen-dependent activation of the prostate-specific antigen (PSA) gene in LNCaP cells, an increase that was not due to an increase in nuclear AR protein levels. Moreover, the viral oncoprotein E1A that inhibits CBP HAT activity fully repressed the ability of HDACIs to stimulate AR-mediated transcription, indicating that CBP is involved in this process. Deletional mutagenesis of AR indicated that whereas the AF-2 domain in the C-terminus is dispensable, the AF-1 domain in the N-terminus is required for augmentation of AR action by HDACIs, an observation which is in concordance with the reduced ability of CBP to activate AR N-terminal deletion mutants. Furthermore, HDACI treatment rescued the deficiency in the transactivation potential of AF-2 mutants. Taken together, our findings suggest that a change in the level of histone acetylation of target genes is an important determinant of AR action, possibly mediated by CBP.
 ...
PMID:Potentiation of androgen receptor transcriptional activity by inhibition of histone deacetylation--rescue of transcriptionally compromised mutants. 1535 Jan 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>