Resveratrol Inhibits Hypoxia-Inducible Factor-1α-Mediated Androgen Receptor Signaling and Represses Tumor Progression in Castration-Resistant Prostate Cancer
Resveratrol Inhibits Hypoxia-Inducible Factor-1α-Mediated Androgen Receptor Signaling and Represses Tumor Progression in Castration-Resistant Prostate Cancer
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DOI：
10.3177/jnsv.60.276
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发表时间：
2014-08-01
影响因子：
1.6
通讯作者：
Yamaji, Ryoichi
中科院分区：
文献类型：
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作者：
Mitani, Takakazu;Harada, Naoki;Yamaji, Ryoichi
雄激素依赖性前列腺癌在雄激素剥夺治疗后不可避免地进展为无法治愈的去势抵抗性前列腺癌（CRPC）。由于去势诱导的缺氧诱导因子（HIF）-1 α在低雄激素水平下增强雄激素受体（AR）的转录活性，模拟去势抵抗阶段，因此HIP-la预期是抑制CRPC生长的有希望的靶标。我们研究了白藜芦醇（3，4 '，5-三羟基-反式-芪）对去势雄性BALB/cSlc-nu/nu小鼠（5周龄）中人前列腺癌LNCaP异种移植物生长的影响。小鼠被给予对照饮食或白藜芦醇饮食（4g/kg饮食）40天。与对照饮食相比，白藜芦醇饮食显著抑制了肿瘤生长。在LNCaP异种移植物中，饮食白藜芦醇降低HIP-1 α的蛋白水平，但不降低AR辅激活因子β-连环蛋白，并降低雄激素应答基因的mRNA水平。在对照组中，β-连环蛋白主要定位于LNCaP异种移植物中HIP-1 α的细胞核中，而膳食白藜芦醇抑制β-连环蛋白的细胞核积累。在模拟去势抵抗阶段的低雄激素水平的缺氧LNCaP细胞中，白藜芦醇抑制缺氧诱导的β-连环蛋白核积累。此外，白藜芦醇抑制HIP-1 α的表达水平，即使在蛋白酶体抑制剂的存在下，抑制缺氧增强的AR反式激活。这些结果表明，膳食白藜芦醇通过降低HIP-1 α表达抑制β-连环蛋白的核定位，可能以蛋白酶体非依赖性方式，并抑制β-连环蛋白介导的AR信号传导;这有助于抑制CRPC的肿瘤生长。
Androgen-dependent prostate cancer inevitably progresses to incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy. Because castration-induced hypoxia-inducible factor (HIF)-1 alpha enhances the transcriptional activity of androgen receptor (AR) at low androgen levels mimicking the castration-resistant stage, HIP-la 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 HIP-1 alpha, but not the AR coactivator beta-catenin, and reduced the mRNA levels of androgen-responsive genes. In the control group, beta-catenin was predominantly localized in the nucleus with HIP-1 alpha in LNCaP xenografts, whereas dietary resveratrol inhibited the nuclear accumulation of beta-catenin. In hypoxic LNCaP cells at a low androgen level mimicking the castration-resistant stage, hypoxia-induced nuclear accumulation of beta-catenin was inhibited by resveratrol. Furthermore, resveratrol repressed the expression level of HIP-1 alpha even in the presence of a proteasome inhibitor and suppressed hypoxia-enhanced AR transactivation. These results indicate that dietary resveratrol represses nuclear localization of beta-catenin by decreasing the HIP-1 alpha expression, perhaps in a proteasome-independent manner, and inhibits beta-catenin-mediated AR signaling; this contributes to suppression of tumor growth of CRPC.