beta-TrCP inhibition reduces prostate cancer cell growth via upregulation of the aryl hydrocarbon receptor.
beta-TrCP inhibition reduces prostate cancer cell growth via upregulation of the aryl hydrocarbon receptor.
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DOI：
10.1371/journal.pone.0009060
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发表时间：
2010-02-05
期刊：
影响因子：
3.7
通讯作者：
Pikarsky E
中科院分区：
文献类型：
--
作者：
Gluschnaider U;Hidas G;Cojocaru G;Yutkin V;Ben-Neriah Y;Pikarsky E
前列腺癌是一种常见的异质性疾病，其中雄激素受体 (AR) 信号在发生和进展中发挥着关键作用。晚期前列腺癌的初始治疗是抑制雄激素信号传导。随后，基本上所有患者都会出现雄激素非依赖性阶段，对抗激素治疗没有反应。因此，需要针对新分子机制的替代策略。 β-TrCP 是一种 E3 连接酶，针对肿瘤发生的许多方面所必需的各种底物。在这里，我们证明 β-TrCP 消耗可抑制前列腺癌，并确定相关的生长控制机制。针对 β-TrCP 的 shRNA 可以减少前列腺癌细胞的生长，并在体外和体内配合雄激素消融。我们发现 β-TrCP 抑制会导致芳烃受体 (AhR) 上调，从而介导治疗效果。这种现象可能与配体无关，因为 AhR 配体 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 不会改变前列腺癌细胞的生长。我们在人类前列腺癌的基底细胞和萎缩上皮细胞中检测到了高 AhR 表达和激活。与良性腺上皮相比，肿瘤细胞中的 AhR 表达和激活也显着更高。这些观察结果表明，AhR 激活可能是前列腺中的一种抗癌机制。我们认为，将 β-TrCP 抑制与雄激素消除相结合可以使晚期前列腺癌患者受益。
Prostate cancer is a common and heterogeneous disease, where androgen receptor (AR) signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. β-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis. Here we show that β-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against β-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that β-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR) mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium. Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining β-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.
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