• Biomolecules & Therapeutics
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• v.22 no.5
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• pp.426-430
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• 2014

Prostate cancer is the most frequently diagnosed cancer. Although prostate tumors respond to androgen ablation therapy at an early stage, they often acquire the potential of androgen-independent growth. Elevated transcriptional activity of androgen receptor (AR) and/or signal transducer and activator of transcription-3 (STAT3) contributes to the proliferation of prostate cancer cells. In the present study, we examined the effect of resveratrol, a phytoalexin present in grapes, on the reporter gene activity of AR and STAT3 in human prostate cancer (LNCaP-FGC) cells stimulated with interleukin-6 (IL-6) and/or dihydrotestosterone (DHT). Our study revealed that resveratrol suppressed the growth of LNCaP-FGC cells in a time- and concentration-dependent manner. Whereas the AR transcriptional activity was induced by treatment with either IL-6 or DHT, the STAT3 transcriptional activity was induced only by treatment with IL-6 but not with DHT. Resveratrol significantly attenuated IL-6-induced STAT3 transcriptional activity, and DHT- or IL-6-induced AR transcriptional activity. Treatment of cells with DHT plus IL-6 significantly increased the AR transcriptional activity as compared to DHT or IL-6 treatment alone and resveratrol markedly diminished DHT plus IL-6-induced AR transcriptional activity. Furthermore, the production of prostate-specific antigen (PSA) was decreased by resveratrol in the DHT-, IL-6- or DHT plus IL-6-treated LNCaP-FGC cells. Taken together, the inhibitory effects of resveratrol on IL-6- and/or DHT-induced AR transcriptional activity in LNCaP prostate cancer cells are partly mediated through the suppression of STAT3 reporter gene activity, suggesting that resveratrol may be a promising therapeutic choice for the treatment of prostate cancer.

• Biomolecules & Therapeutics
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• v.29 no.6
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• pp.667-677
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• 2021

The elevated expression of the hyaluronan-mediated motility receptor (HMMR) is known to be highly associated with tumor progression in prostate cancer, but the molecular mechanisms underlying the regulation of HMMR expression remain unclear. Here, we report that mammalian target of rapamycin (mTOR) is a key regulator of HMMR expression, for which its kinase activity is required. Pharmacological inhibitors of mTOR, such as rapamycin and Torin2, markedly suppressed the mRNA level as well as the protein level of HMMR in LNCaP and PC-3 cells. Our data demonstrate that such regulation occurs at the transcription level. HMMR promoter reporter assays revealed that the transcription factor SRF is responsible for the mTOR-mediated transcriptional regulation of HMMR gene. Consistently, the suppression of HMMR expression by Torin2 was noticeably reversed by the overexpression of SRF. Moreover, our findings suggest that the SRF binding sites responsible for the transcriptional regulation of HMMR through the mTOR-SRF axis are located in HMMR promoter sequences carrying the first intron, downstream of the translational start site. Furthermore, the upregulation of HMMR by DHT was abolished by stimulation with rapamycin, prior to DHT treatment, suggesting that mTOR activity is required for the induction of HMMR expression by androgen. Collectively, our study provides new mechanistic insights into the role of mTOR/SRF/AR signaling in HMMR regulation in prostate cancer cells.

• Molecules and Cells
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• v.28 no.1
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• pp.67-71
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• 2009

Estrogen receptor ${\alpha}$ ($ER{\alpha}$) mediates the mitogenic effects of estrogen. $ER{\alpha}$ signaling regulates the normal growth and differentiation of mammary tissue, but uncontrolled $ER{\alpha}$ activation increases the risk to breast cancer. Estrogen binding induces ligand-dependent $ER{\alpha}$ activation, thereby facilitating $ER{\alpha}$ dimerization, promoter binding and coactivator recruitment. $ER{\alpha}$ can also be activated in a ligand-independent manner by many signaling pathways, including protein kinase A (PKA) signaling. However, in several $ER{\alpha}$-positive breast cancer cells, PKA inhibits estrogen-dependent cell growth. FoxH1 represses the transcriptional activities of estrogen receptors and androgen receptors (AR). Interestingly, FoxH1 has been found to inhibit the PKA-induced and ligand-induced activation of AR. In the present study, we examined the effects of PKA activation on the ability of FoxH1 to represses $ER{\alpha}$ transcriptional activity. We found that PKA increases the protein stability of FoxH1, and that FoxH1 inhibits PKA-induced and estradiol-induced activation of an estrogen response element (ERE). Furthermore, in MCF7 cells, FoxH1 knockdown increased the PKA-induced and estradiol-induced activation of the ERE. These results suggest that PKA can negatively regulate $ER{\alpha}$, at least in part, through FoxH1.

• Journal of Life Science
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• v.21 no.4
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• pp.481-485
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• 2011

T0901317 is a potent synthetic ligand for liver X receptor (LXR, NR1H2/3), a member of the nuclear receptor superfamily that functions as a transcription factor. However, T0901317 has been also reported to modulate the activity at least four other nuclear receptors (NRs), acting as agonists for farnesoid X receptor (FXR, NR1H4) and pregnane X receptor (PXR, NR1I2) and as antagonists for androgen receptor (AR, NR3C4) and retinoid-related orphan receptor-${\alpha}$ (ROR-${\alpha}$, NR1F1). We report here that T0901317 can also function as an inhibitor for constitutive androstane receptor (CAR, NR1I3). Since CAR is a major player of xenobiotic and cholesterol metabolism in the liver, along with PXR, FXR and LXR, which are reported to be regulated by T0901317, this further complicates the interpretation of potential results with T0901317 in liver cells.

• 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.

• Journal of Life Science
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• v.29 no.10
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• pp.1159-1163
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• 2019

Although there is a growing interest in male menopause, a phenomenon associated with male hormone depletion, current kits using antibodies to quantify male hormones are expensive. In this study, we constructed an in vitro system for verifying the activity or concentration of male steroid hormones using a transcriptional activity test. A reporter plasmid, pGL2-Neo-ARE-AdE1BTATA, which reacts to testosterone, was constructed. In this plasmid, the ARE-AdE1bTATA sequences can be bounded by the testosterone - androgen receptor complex to express luciferase as a reporter. Then, a stable transfection was performed on the human prostate cancer cell line, LNcap-LN3. The constructed LNcap-LN3/pGL2-Neo-ARE-AdE1BTATA testosterone compound detection (TCD) system showed quantitatively proportional luciferase activities to concentrations of $10^{-13}$ to $10^{-8}M$ of standard testosterone. The established in vitro TCD system will contribute to the development of materials for health/functional foods and drugs as it will be possible to search en masse for testosterone-like or testosterone-inhibiting substances derived from natural materials.