title: Resveratrol inhibits hypoxia-inducible factor-1α-mediated androgen receptor signaling and represses tumor progression in castration-resistant prostate cancer.
abstract: Androgen-dependent prostate cancer inevitably progresses to incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy. Because castration-induced hypoxia-inducible factor (HIF)-1α enhances the transcriptional activity of androgen receptor (AR) at low androgen levels mimicking the castration-resistant stage, HIF-1α is expected to be a promising target for suppression of growth of CRPC. We investigated the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene) on the growth of human prostate cancer LNCaP xenografts in castrated male BALB/cSlc-nu/nu mice (5 wk old). The mice were administered a control diet or a resveratrol diet (4 g/kg diet) for 40 d. The resveratrol diet significantly suppressed tumor growth compared to the control diet. In LNCaP xenografts, dietary resveratrol decreased the protein level of HIF-1α, but not the AR coactivator β-catenin, and reduced the mRNA levels of androgen-responsive genes. In the control group, β-catenin was predominantly localized in the nucleus with HIF-1α in LNCaP xenografts, whereas dietary resveratrol inhibited the nuclear accumulation of β-catenin. In hypoxic LNCaP cells at a low androgen level mimicking the castration-resistant stage, hypoxia-induced nuclear accumulation of β-catenin was inhibited by resveratrol. Furthermore, resveratrol repressed the expression level of HIF-1α even in the presence of a proteasome inhibitor and suppressed hypoxia-enhanced AR transactivation. These results indicate that dietary resveratrol represses nuclear localization of β-catenin by decreasing the HIF-1α expression, perhaps in a proteasome-independent manner, and inhibits β-catenin-mediated AR signaling; this contributes to suppression of tumor growth of CRPC.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University.
authors.forename: Takakazu
authors.initials: T
authors.lastname: Mitani
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanimori
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inui
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002467:Cell Nucleus; D004032:Diet; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D015533:Transcriptional Activation; D027843:Vitis / Q000737:chemistry; D051176:beta Catenin / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010936:Plant Extracts; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013267:Stilbenes; D051176:beta Catenin; D000077185:Resveratrol