• Molecules and Cells
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• v.28 no.3
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• pp.189-194
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• 2009

The modulating effect of IGF-I on the regulation of AR gene expression and activation in skeletal muscle cells remains poorly understood. In this study, the effects of IGF-I treatment on AR induction and activation in the absence of AR ligands were examined. Differentiating C2C12 cells were treated with different concentrations (0-250 ng/ml) of IGF-I or for various periods of time (0-60 min) of 250 ng/ml IGF-I. Treatment of C2C12 cells with IGF-I resulted in a dose- and time-dependent increase in total AR and phosphorylated AR (Ser 213). IGF-I treatment also led to significantly increased AR mRNA expression when compared with the control. The levels of skeletal ${\alpha}-actin$ and myogenin mRNA, known target genes of AR, were also significantly upregulated after 5 or 10 min of treatment with IGF-I. Confocal images revealed that IGF-I stimulated nuclear localization of AR in the absence of ligands. In addition, an electrophoretic mobility shift assay indicated that IGF-I stimulated the AR DNA binding activity in a time-dependent manner. The present results suggest that IGF-I stimulates the expression and activation of AR by ligand-independent mechanism in differentiating C2C12 mouse skeletal muscle cells.

• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.210-218
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• 2023

Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.

• Bulletin of the Korean Chemical Society
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• v.33 no.1
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• pp.111-114
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• 2012

Androgen receptor (AR) is ligand-inducible nuclear hormone receptor which has been focused on key molecular target in growth and progression of prostate cancer. We synthesized a series of 4-aryl 2-substituted aniline-thiazole analogs and evaluated their anti-cancer activity in AR-dependent human prostate cancer LNCap cells. Among them, the compound 6 inhibited the tumor growth in LNCap-inoculated xenograft model.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3321-3324
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• 2016

Background: Androgen receptors (ARs) are expressed in more than 70% of breast cancers (BCs) and have been implicated in BC pathogenesis. Some triple negative (TN)BC tumors express AR and may benefit from AR-targeted therapies. The aim of this study was to evaluate survival and the prevalence of AR expression and its correlation with other risk factors in triple negative BCs in women from Western Iran. Materials and Methods: In a retrospective study between 2009-2015, 41 patients with TNBC were referred to the Private Clinic of Oncology, Kermanshah city, Iran. ER, PR and AR-positive expression was defined as ${\geq}10%$ nuclear staining and also HER2 (2+), FISH was performed. Nuclear staining was considered representative for Ki67 and P53. The mean follow-up for the patients was 25 months. In this time, 5 patients died and 4 lost to follow-up were censored from survival analysis. Results: The mean age at diagnosis was 46.9 years (range, 24-71 years) and all patients were female. The OS rates for AR-positive and AR-negative patients were 90% and 85.1%, respectively, and the mean OS was 26.3 and 23.2 months. Therefore, there was no significant difference between the two groups (Hazard ratio: 0.580, 95% CI: 0.086-3.893, P=0.575). Conclusions: In TNBC patients, evaluation of AR status may provide additional information on prognosis and treatment. The results of studies showed that the prevalence AR expression may differ in the world and probably ethnicity can be an influencing factor.

• Journal of Food Hygiene and Safety
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• v.38 no.5
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• pp.305-310
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• 2023

This study aimed to determine the human androgen receptor (AR)-mediated endocrine disrupting potential of parabens and triclosan in food and household products using a cell-based assay in the OECD TG No.458, the 22Rv1/MMTV_GR-KO transcriptional activation assay. Four parabens (methyl-, ethyl-, propyl-, and butyl-) are determined as AR antagonists in OECD TG No.458. However, their AR antagonistic effects were not exhibited in the presence of the S9 hepatic fraction. Triclosan is also classified as an AR antagonist, and the AR antagonistic effect induced by triclosan significantly decreased in the presence of the phase I + II S9 fraction. Regarding the mechanism of AR antagonism induced by parabens and triclosan, the AR-mediated endocrine disrupting effects were exhibited through suppressing the translocation of ligand-bound AR to the nucleus via blocking of AR dimerization in the cytosol. These results indicate that the four parabens and triclosan have AR-mediated endocrine disrupting potential through an AR antagonistic effect via inhibiting AR dimerization; however, their endocrine disrupting effects deceased in the presence of hepatic metabolic enzymes.

• Nutrition Research and Practice
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• v.16 no.4
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• pp.419-434
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• 2022

BACKGROUND/OBJECTIVES: Benign prostatic hyperplasia (BPH) is the most common prostate disease and one of the most common chronic diseases caused by aging in men. On the other hand, there has been no research on BPH using Abeliophyllum distichum Nakai (A. distichum). Therefore, this study investigated the effects of A. distichum on BPH. MATERIALS/METHODS: A. distichum leaves were extracted with distilled water, 70% ethanol, and 95% hexane as solvents. Subsequently, the inhibitory effects of each A. distichum extract on androgen receptor (AR) signaling were evaluated in vitro. The testosterone-induced BPH model was then used to confirm the efficacy of A. distichum leaves in 70% ethanol extract (ADLE). RESULTS: ADLE had the strongest inhibitory effect on AR signaling. A comparison of the activity of ADLE by harvest time showed that the leaves of A. distichum harvested in autumn had a superior inhibitory effect on AR signaling to those harvested at other times. In the BPH rat model, the administration of ADLE reduced the prostate size and prostate epithelial cell thickness significantly and inhibited AR signaling. Subsequently, the administration of ADLE also reduced the expression of growth factors, thereby inactivating the PI3K/AKT pathway. CONCLUSIONS: An analysis of the efficacy of ADLE to relieve BPH showed that the ethanol extract grown in autumn exhibited the highest inhibitory ability of the androgen-signaling related factors in vitro. ADLE also inhibited the expression of growth factors by inhibiting the expression of the androgen-signaling related factors in vivo. Overall, ADLE is proposed as a functional food that is effective in preventing BPH.

• Journal of Ginseng Research
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• v.46 no.3
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• pp.473-480
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• 2022

Background: Benign prostatic hyperplasia (BPH) is a disease characterized by abnormal proliferation of the prostate, which occurs frequently in middle-aged men. In this study, we report the effect of red ginseng oil (KGC11o) on BPH. Methods: The BPH-induced Sprague-Dawley rats were divided into seven groups: control, BPH, KGC11o 25, 50, 100, 200, and finasteride groups. KGC11o and finasteride were administered for 8 weeks. The BPH biomarkers, DHT, 5AR1, and 5AR2, androgen receptor, prostate-specific antigen (PSA), Bax, Bcl-2, and TGF-β were determined in the serum and prostate tissue. The cell viability after KGC11o treatment was determined using BPH-1 cells, and, androgen receptor, Bax, Bcl-2, and TGF-β were confirmed by western blotting. Results: In the in vivo study, administration of KGC11o reduced prostate weight by 18%, suppressed DHT (up to 22%) and 5AR2 (up to 12%) levels from administration of 100 mg/kg KGC11o (P < 0.05). PSA was significantly downregulated dose-dependently from at the concentration of 50 mg/kg KGC11o (P < 0.05). BPH-1 cell viability significantly reduced through the treatment with KGC11o. In vitro and vivo, AR, Bcl-2 TGF-β levels reduced significantly but Bax was increased (P < 0.05). Conclusion: These results suggest that KGC11o may inhibit the development of BPH by significantly reducing the levels of BPH biomarkers via 5ARI, anti-androgenic effect, and anti-proliferation effect, serving as a potential functional food for treating BPH.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.5
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• pp.1154-1160
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• 2009

Androgen receptors (AR) play a crucial role in the development and progression of prostate cancer. Many studies have suggested that prostate cancer cell proliferation is inhibited by AR downregulation, and it has been reported that Takrisodokyeum (TRSDY) induced apoptotic cell death and suppressed tumorigenesis in human leukemia cells. Therefore, this study was conducted to elucidate the mechanism by which TRSDY affects cell growth and AR expression in androgen-dependent prostate cancer cells (LNCaP cells). We investigated the proliferation and apoptosis of LNCaP cells using MTT and DNA fragmentation assays. In addition, we used western blot analysis to assess the effects of TRSDY on the expression of the AR target gene, prostate-specific antigen (PSA). Furthermore, the mechanism of AR downregulation by TRSDY was investigated using EMSA to analyze the binding activity of AR to androgen response elements (ARE). TRSDY significantly suppressed proliferation and induced apoptosis in LNCaP cells. In addition, TRSDY-induced apoptotic cell death was accompanied by activation of caspase-3 and cleavage of its substrate, poly(ADP-ribose) polymerase. TRSDY also inhibited the constitutively expressed- or 5a-dihydrotestosterone (DHT)-induced AR/PSA protein levels. However, these effects were mediated by inhibition of the binding of AR to ARE. TRSDY-mediated AR/PSA downregulation contributes to the inhibition of cell proliferation and the induction of apoptosis in LNCaP human prostate cancer cells. Our findings suggest that TRSDY may be used as a chemopreventive or chemotherapeutic agent for the treatment of prostate cancer.

• Development and Reproduction
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• v.13 no.3
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• pp.133-143
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• 2009

Pivotal roles of steroid hormones in uterine endometrial function are well established from the mouse models carrying the null mutation of their receptors. Literally androgen belongs to male but interestingly it also detected in female. The fluctuations of androgen levels are observed during reproductive cycle and pregnancy, and the functional androgen receptor is expressed in reproductive organs including uterus. Using high throughput methodology, the downstream genes of androgen have been isolated and revealed correlations between other steroid hormones. In androgen-deficient mice, uterine responses to exogenous gonadotropins are impaired and the number of pups per litter is reduced dramatically. As expected androgen has important role in decidual differentiation through AR. It regulates specific gene network during those cellular responses. Recently we examined the effects of steroid hormonal complex containing high level of androgen. Interestingly, on the contrary to the androgen-alone administration, the hormonal complex did not disturb the decidual reaction and the pubs did not show any morphological abnormality. It is suspected that the complexity of communication between other steroid hormone and their receptors are the reasons. In summary, androgen exists in female blood and it suggests the importance of androgen in female reproduction. However, the complex interactions with other hormones are not fully understood compared with estrogen and progesterone. The further studies to evaluate the possible role of androgen are needed and important to provide the in vivo rational for the prevention of associated pregnancy complications and help human's health.

• Food Science and Biotechnology
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• v.16 no.3
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• pp.457-462
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• 2007

Histone acetyltransferase (HAT) is a family of enzymes that regulate histone acetylation. Dysfunction of HAT plays a critical role in the development of cancer. Here we have screened the various plant extracts to find out the potent HAT inhibitors. The bellflower (Platycodon grandiflorum) root have exhibited approximately 30% of the inhibitory effects on HAT activity, especially p300 and CBP (CREB-binding protein) at the concentration of $100\;{\mu}g/mL$. The cell viability was decreased approximately 52% in LNCaP cell for 48 hr incubation. Furthermore, mRNA level of 3 androgen receptor target genes, PSA, NKX3.1, and TSC22 were decreased with bellflower root extract treatment ($100\;{\mu}g/mL$) in the presence of androgen. In ChIP assay, the acetylation of histone H3 and H4 in PSA promoter region was dramatically repressed by bellflower root treatment, but not TR target gene, Dl. Therefore, the potent HAT inhibitory effect of bellflower root led to the decreased transcription of AR target genes and prostate cancer cell growth with the repression of histone hyperacetylation.