Resveratrol Down-Regulates the Androgen Receptor at the Post-Translational Level in Prostate Cancer Cells

Harada, Naoki; Murata, Yohei; Yamaji, Ryoichi; Miura, Takumi; Inui, Hiroshi; Nakano, Yoshihisa

doi:10.3177/jnsv.53.556

Cited by 42 publications

(46 citation statements)

References 22 publications

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“…1,2 Resveratrol inhibits cancer cell growth in many cell lines, including cancers of the lung, prostate, colon, breast and ovaries. [3][4][5][6][7][8][9][10][11][12][13][14] Resveratrol also reduces tumor incidence in animal models by interfering with carcinogenesis through a wide array of anti-cancer actions. Several animal studies have demonstrated the ability of resveratrol to inhibit prostate cancer development by downregulating androgen receptors, inducing apoptosis/cell cycle arrest and inhibiting disease progression.…”

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confidence: 99%

Red wine consumption and risk of prostate cancer: The California Men's Health Study

Chao

Haque

Eeden

et al. 2009

Intl Journal of Cancer

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Red wine contains polyphenol antioxidants that inhibit prostate cancer development in animal studies. We investigated the effect of red wine intake on the risk of prostate cancer using data prospectively collected in the California Men's Health Study (CMHS). CMHS is a multiethnic cohort of 84,170 men aged 45-69 years who were members of the Kaiser Permanente Southern and Northern California Health Plans. Information on demographic and lifestyle factors was collected using mailed questionnaires between 2002 and 2003. We used Cox models to estimate the effect of red wine on prostate cancer risk, adjusting for potential confounders. A total of 1,340 incident prostate cancer cases identified from Surveillance, Epidemiology and End Result-affiliated cancer registries were included in the analyses. We did not find a clear association between red wine intake and risk of prostate cancer. Hazard ratio (HR) estimates for consuming <1 drink/week, 1 drink/week but <1 drink/day and 1 drink/day were 0.89, 95% confidence interval (0.74-1.07), 0.99 (0.83-1.17) and 0.88 (0.70-1.12), respectively. Further, we observed no linear dose response. The lack of association for red wine intake was consistently observed when we restricted the analyses to those with and without a history of PSA screening. In addition, we also did not observe any association with prostate cancer for beer, white wine, liquor or combined alcoholic beverage intake (HR for combined alcoholic beverage intake of 5 drinks/day 5 1.16 (0.83-1.63). Neither red wine nor total alcohol consumption were associated with prostate cancer risk in this population of moderate drinkers.Red wine is a rich source of polyphenol antioxidants such as resveratrol. Recently, resveratrol has received considerable attention because of its potent anti-cancer properties.

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Red wine consumption and risk of prostate cancer: The California Men's Health Study

Chao

Haque

Eeden

et al. 2009

Intl Journal of Cancer

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“…Till to date, multidirectional studies attempting to unravel the biochemical basis of chemoprevention and chemotherapy with resveratrol have revealed that the compound (i) prevents the activation of various carcinogens, (ii) protects cellular macromolecules from oxidative damage, (iii) activates the carcinogen detoxification pathways, (iv) attenuates inflammatory responses, (v) inhibits proliferation of cancer cells, (vi) induces apoptosis selectively in cancer cells, (vii) impedes the angiogenic and metastatic progression, and (viii) enhances the sensitivity of cancer cells to conventional chemotherapy and radiotherapy (Kundu and Surh, 2008). Previous studies have demonstrated that resveratrol inhibits the proliferation and induces apoptosis in various prostate cancer cells (Mitchell et al, 1999;Narayanan et al, 2003;Harada et al, 2007). Resveratrol attenuated the growth of prostate tumors in a transgenic rat adenocarcinoma of prostate (TRAMP) model.…”

Section: Discussionmentioning

confidence: 99%

“…Biomol Ther 22(5), 426-430 (2014) www.biomolther.org that resveratrol attenuates the proliferation of LNCaP prostate cancer cells by downregulating AR protein expression following transcriptional (Mitchell et al, 1999) or post-translational (Harada et al, 2007) mechanisms. However, a molecular link between the inhibitory effect of resveratrol on STAT3 signaling and the downregulation of AR has not been established.…”

Section: Original Articlementioning

confidence: 99%

“…Resveratrol (3,5,, a phytoalexin ab undantly present in grapes and other medicinal plants, has been extensively investigated for its chemopreventive and chemotherapeutic potential (Shankar et al, 2007;Kundu and Surh, 2008). Previous studies have shown that resveratrol inhibits the androgen-dependent or -independent growth of prostate cancer cells (Mitchell et al, 1999;Harada et al, 2007). Kotha et al reported that resveratrol induced apoptosis in human prostate cancer (DU145) cells by blocking STAT3 signaling pathway (Kotha et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

Lee¹,

Kundu²,

Keum³

et al. 2014

Biomol Ther

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.biomolther.orgProstate 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 DHTinduced 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.

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“…We have found that resveratrol inhibits AR transactivation without binding to the LBD of AR. 13) We also found that resveratrol inhibited the N-C interaction of AR in human prostate cancer PC-3 cells (N. Harada, unpublished data). Taken together, our data indicate that the N-C/ -catenin system can detect not only androgenic and anti-androgenic compounds that bind to the LBD of AR, but also compounds that inhibit the N-C interaction in ways that do not involve binding to the LBD.…”

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confidence: 90%

A Yeast Bioassay for Androgenic and Anti-Androgenic Compounds Based on the NH₂- and COOH-Terminal Interaction of Androgen Receptor

Ogawa

Yamaji

Mitani

et al. 2010

Bioscience, Biotechnology, and Biochemistry

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Androgenic compounds induce an interaction between the NH 2 -and COOH-terminal regions (N-C interaction) of androgen receptor (AR). We describe a rapid yeast bioassay for androgenic and anti-androgenic compounds based on androgen-dependent -catenin-enhanced N-C interaction. The bioassay was also effective at detecting compounds that inhibit the N-C interaction in ways that do not involve binding to the ligand-binding domain.Key words: androgen receptor (AR); bioassay; N-C interaction; -catenin; yeast two-hybridAndrogens such as testosterone and its metabolite dihydrotestosterone (DHT) act through binding to the androgen receptor (AR) not only in physiological processes such as male sexual differentiation and the development of bone, muscle, and reproductive tissues, but also in pathophysiological processes such as prostate tumor growth. 1) Androgen-bound AR interacts with androgen response elements (AREs) in the promoters of target genes and functions as a transcriptional factor. The recruitment of coactivators to AR enhances AR transactivation. The AR possesses three functional domains: an NH 2 -terminal domain (NTD), a central DNA-binding domain, and a COOH-terminal ligandbinding domain (LBD).2) The binding of ligands to the LBD triggers intramolecular or intermolecular interaction between the NH 2 -and COOH-terminal regions (N-C interaction) of the AR. The N-C interaction is enhanced by certain coactivators including -catenin, 3) ARA24/Ran, 4) and p160 family proteins such as steroid receptor coactivator-1 (SRC-1) 5) and transcriptional intermediate factor-2 (TIF-2), 3) and is required for proper and maximal AR transactivation.AR agonists and antagonists are expected to be effective for the prevention of male osteoporosis and for the inhibition of prostate cancer growth respectively. 6,7) Accordingly, several bioassays for the detection of androgenic and anti-androgenic compounds have been developed using both mammalian and yeast cells. Mammalian-based assays have higher sensitivity for detection of androgenic activity than yeast-based assays, but yeast-based assays are simpler, more rapid, and cheaper than mammalian-based assays. Furthermore, there is no contamination of steroids in yeast-based assays, whereas in mammalian-based assays, steroidal compounds must be removed from the media because fetal bovine serum including various steroids is added to them.Previous yeast bioassays based on interaction between a coactivator and the LBD of AR require grinding of cells and the addition of substrate for the reporter gene product (usually -galactosidase), which is timeconsuming and costly. To avoid these problems, a new yeast bioassay using a green fluorescent protein (GFP) as a reporter gene has been developed. However, the 50% effective concentration (EC 50 ) values of various steroids, including testosterone and DHT, are higher in bioassays using GFP than in bioassays usinggalactosidase. Here, we describe a new yeast bioassay based on the androgen-dependent N-C interaction, which is enhanced by -catenin and mo...

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Resveratrol Down-Regulates the Androgen Receptor at the Post-Translational Level in Prostate Cancer Cells

Cited by 42 publications

References 22 publications

Red wine consumption and risk of prostate cancer: The California Men's Health Study

Red wine consumption and risk of prostate cancer: The California Men's Health Study

Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

A Yeast Bioassay for Androgenic and Anti-Androgenic Compounds Based on the NH₂- and COOH-Terminal Interaction of Androgen Receptor

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Resveratrol Down-Regulates the Androgen Receptor at the Post-Translational Level in Prostate Cancer Cells

Cited by 42 publications

References 22 publications

Red wine consumption and risk of prostate cancer: The California Men's Health Study

Red wine consumption and risk of prostate cancer: The California Men's Health Study

Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

A Yeast Bioassay for Androgenic and Anti-Androgenic Compounds Based on the NH2- and COOH-Terminal Interaction of Androgen Receptor

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A Yeast Bioassay for Androgenic and Anti-Androgenic Compounds Based on the NH₂- and COOH-Terminal Interaction of Androgen Receptor