Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression
Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression
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DOI：
10.1038/onc.2009.322
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发表时间：
2010-01-14
期刊：
影响因子：
8
通讯作者：
Naito, S.
中科院分区：
文献类型：
--
作者：
Shiota, M.;Yokomizo, A.;Naito, S.
几乎没有成功的治疗去势抵抗前列腺癌(CRPC)的方法。近年来，CRPC被认为是雄激素/雄激素受体(AR)信号通路增强的结果，其中大部分AR过度表达。在本研究中，碱性螺旋-环-螺旋转录因子和AR的成员Twist1被过氧化氢上调，而加入N-乙酰-L-半胱氨酸和Twist1被敲除后，上调的反应被取消。此外，抗去势的LNCaP衍生物和抗过氧化氢的LNCaP衍生物表现出相似的表型。然后，去势和AR基因敲除都增加了细胞内的活性氧水平。此外，Twist1通过与AR启动子区域的E-box结合来调节AR的表达。沉默Twist1通过诱导细胞周期停滞于G1期和细胞凋亡，抑制AR表达的LNCaP细胞和抗去势LNCaP衍生物的细胞生长。这些发现表明，去势诱导的氧化应激可能通过Twist1的过度表达促进AR的过度表达，从而导致对去势的抵抗力的增强。调节去势诱导的氧化应激或Twist1/AR信号可能是开发前列腺癌新疗法的有用策略，即使在CRPC中也是如此，CRPC通过过度表达AR而依赖AR信号。Oncogene(2010年)29237250；doi：10.1038/onc.2009.322；2009年10月5日在线发布
There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR. Oncogene (2010) 29, 237-250; doi:10.1038/onc.2009.322; published online 5 October 2009