Quercetin inhibits the expression and function of the androgen receptor...
Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity.
Rimler A, Culig Z, Levy-Rimler G, Lupowitz Z, Klocker H, Matzkin H, Bartsch G, Zisapel N.
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
BACKGROUND: The androgen receptor (AR) promotes growth and functionality of androgen sensitive benign and cancer tissues. The pineal hormone melatonin is an androgen protagonist in vivo and in vitro. The interference of melatonin in the AR cascade was explored. METHODS: The effects of melatonin on AR expression, level, agonist and androgen-response element (ARE) binding, reporter gene activity and intracellular localization were explored in prostate cancer LNCaP cell line. RESULTS: Melatonin increased immunoreactive AR cells in the absence and presence of dihydrotestosterone. Despite this increase and maintenance of AR agonist binding capacity, the androgen-induced reporter gene activity and suppression of AR-mRNA were attenuated.
Immunocytochemical analysis and subcellular fractionation studies revealed nuclear exclusion of AR by melatonin.
CONCLUSIONS: The melatonin-mediated nuclear exclusion of the AR may explain the attenuation of AR activity in the prostate cancer cells. This is the first demonstration of a hormone-induced mislocalization of the AR in prostate epithelial cells and may represent a novel route for regulating AR activity. Copyright 2001 Wiley-Liss, Inc.
*The doses used to downregulate androgen receptor activity is very high, and involved the equivilant of 1mg per every kilogram of bodyweight. However the sleep effects of melatonin are not dose dependent, (3mg works as well as 50mg.), and the same possibly apply to androgen receptor activity as well.
Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells.
Rimler A, Lupowitz Z, Zisapel N.
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University; Tel Aviv 69978 Israel.
OBJECTIVES: The pineal hormone melatonin inhibits the growth of benign human prostate epithelial cells and the androgen-dependent prostate cancer LNCaP cells. In the androgen-nonresponsive prostate carcinoma PC3 cells melatonin inhibits cell growth only at high but not low cell density. We have recently found that melatonin causes nuclear exclusion of the AR and attenuates it transcriptional activity in LNCaP cells as well as PC3 cells stably transfected with a wild type AR expressing vector (PC3-AR). The aim of this study was to investigate whether melatonin inhibits effects of AR on cell growth in PC3-AR cells and whether inhibition of AR DNA binding is involved. METHODS: The effects of androgen, melatonin and their combination on the growth of the PC3-AR cells and on AR DNA binding in PC3-AR and LNCaP cells were studied. RESULTS: DHT suppressed cell growth in the PC3-AR cells and enhanced AR binding to the androgen responsive element (ARE). Melatonin had no effect on cell growth in the absence of DHT but counteracted the androgen-induced inhibition at low androgen concentrations. Melatonin did not suppress and even slightly enhanced the capacity of AR binding to the ARE in the PC3-AR as well as in LNCaP cells. CONCLUSIONS: Attenuation by melatonin of AR activity in the prostate cancer cells is not due to suppression of AR binding to the ARE, and is presumably caused by its effects on AR protein interaction and intracellular trafficking.
Effect of essential oils, such as raspberry ketone and its derivatives, on antiandrogenic activity based on in vitro reporter gene assay.
Ogawa Y, Akamatsu M, Hotta Y, Hosoda A, Tamura H.
Department of Environmental Bioscience, Meijo University, Nagoya 468-8502, Japan.
The effect of essential oils, such as raspberry ketone, on androgen (AR) receptor was investigated using a MDA-kb2 human breast cancer cell line for predicting potential AR activity. Among them, eugenol had the highest AR antagonistic activity with its IC(50) value of 19 microM. Raspberry ketone, which has threefold higher anti-obese activity than that of capsaicin, also had AR antagonist activity with its IC(50) value of 252 microM. Based on these findings, a more precise CoMFA model was proposed as follows: pIC(50) [log (1/IC(50))]=3.77+[CoMFA field terms] (n=39, s=0.249, r(2)=0.834, s(cv)=0.507, q(2)=0.311 (three components).
Novel Anti-Prostate Cancer Curcumin Analogues that Enhance Androgen Receptor Degradation Activity.
Shi Q, Shih CC, Lee KH.
AndroScience Corporation, San Diego, CA, 91121 USA
The androgen receptor (AR) plays a crucial role in the physiological and pathological functions of androgen. As a transcription factor, the AR modulates androgen activity by regulating the transcription of target genes that are involved in numerous physiological functions and pathological disorders, such as acne vulgaris, androgenetic alopecia, benign prostate hyperplasia (BPH), and prostate cancers. Although many natural and synthetic curcumin analogues have been reported to possess anticancer activity through a common cytotoxic property against proliferating tumor cells, none has been reported to inhibit cancer cell growth through a more specific mechanism or target in the cancer cells. Recently, curcumin analogues were studied extensively regarding their synthesis, structure-activity (i.e., anticancer activity) relationships, and mechanism of action. These compounds, such as ASC-J9 and its analogues (3 and 4), have now been shown to inhibit prostate cancer proliferation through a novel mechanism of enhancing AR degradation.
Curcumin Blocks the Activating of Androgen and Interlukin-6 on Prostate Specific Antigen Expression in Human Prostatic Carcinoma Cells
Ke-Hung Tsui , Tsui-Hsia Feng , Chang-Mei Lin , Phei-Lang Chang , and Horng-Heng Juang *
Curcumin, a naturally occurring compound, exhibits anti-cancer chemopreventive effects. We evaluated the effects and mechanisms of curcumin on the gene expression of prostate-specific antigen (PSA) in human androgen-sensitive prostatic carcinoma cells. LNCaP cells were used to determine the effect of curcumin on PSA expression. Quantitative PSA expressions were assessed using RT-PCR, enzyme linked immunosorbent assay (ELISA), and immunoblot assay. The modulation of androgen, interlukin-6 (IL-6) and prostate-derived Ets factor (PDEF) on PSA gene was identified by transient gene expression assay using a PSA reporter vector. The effect of curcumin on the activity of androgen receptor was evaluated using electrophoretic mobility shift assay (EMSA). Immunoblot assays, RT-PCR, and ELISA indicated that curcumin treatments blocked the stimulation of methyltrienolone (R1881) and IL-6 on PSA gene expression in LNCaP cells. The effects of curcumin appear to be mediated via the androgen response element of PSA gene. Results from immunoblot assay and EMSA revealed the modulation of curcumin on the expression of androgen receptor and androgen receptor binding activity on androgen response element of PSA gene. Although overexpression of PDEF dramatically enhanced PSA gene expression, the results of immunoblot assays and transient reporter assays indicated that curcumin treatments did not affect the gene expression of PDEF. Curcumin inhibits R1881- and IL-6-mediated expression of PSA gene expression in LNCaP cells through the downregulation of the expression and activity of androgen receptor.
Inhibitory effect of acetyl-11-keto-?-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells
Androgen receptor (AR)-mediated signaling is crucial for the development and progression of prostate cancer (PCa). Naturally occurring phytochemicals that target the AR signaling offer significant protection against this disease. Acetyl-11-keto-?-boswellic acid (AKBA), a compound isolated from the gum-resin of Boswellia carterii, caused G1-phase cell cycle arrest with an induction of p21WAF1/CIP1, and a reduction of cyclin D1 as well in prostate cancer cells. AKBA-mediated cellular proliferation inhibition was associated with a decrease of AR expression at mRNA and protein levels. Furthermore, the functional biomarkers used in evaluation of AR transactivity showed suppressions of prostate-specific antigen promoter-dependent and androgen responsive element-dependent luciferase activities. Additionally, down-regulation of an AR short promoter mainly containing a Sp1 binding site suggested the essential role of Sp1 for the reduction of AR expression in cells exposed to AKBA. Interruption effect of AKBA on Sp1 binding activity but not Sp1 protein levels was further confirmed by EMSA and transient transfection with a luciferase reporter driven by three copies of the Sp1 binding site of the AR promoter. Therefore, anti-AR properties ascribed to AKBA suggested that AKBA-containing drugs could be used for the development of novel therapeutic chemicals.
Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells
Messing, Edward M.,
Although epidemiological evidence indicates that a daily supplement of vitamin E may reduce the risk of prostate cancer, the detailed mechanism underlying this effect remains unclear. Here we demonstrate that ?-tocopheryl succinate (VES) can suppress the expression of prostate-specific antigen (PSA), a marker for the progression of prostate cancer. VES can also suppress androgen receptor (AR) expression by means of transcriptional and posttranscriptional modulation, but not ligand binding, nuclear translocation, or AR dimerization. This VES-mediated inhibition of AR is selective because VES does not repress the expression of other nuclear receptors. Cell growth studies further show that VES inhibits the growth of prostate cancer LNCaP cells. In contrast, hydroxyflutamide (HF), an antiandrogen currently used to treat prostate cancer patients, only slightly inhibits LNCaP cell growth. Interestingly, simultaneous addition of HF and VES results in a more significant inhibition of LNCaP cell growth. Moreover, selenomethionine (SM), a prostate cancer treatment adjuvant, shows an inhibitory effect on LNCaP cell growth, yet has no effect on the AR/PSA pathway. Together, our data indicate that VES may suppress androgen/AR-mediated cell growth and PSA expression by inhibiting AR expression at both the transcription and translation levels. This previously undescribed mechanism may explain how VES inhibits the growth of prostate cancer cells and help us to establish new therapeutic concepts for the prevention and treatment of prostate cancer.
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