Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells.
Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells.
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DOI：
10.1038/onc.2012.561
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发表时间：
2014-01-02
期刊：
影响因子：
8
通讯作者：
Larner JM
中科院分区：
文献类型：
--
作者：
Sarkar S;Brautigan DL;Parsons SJ;Larner JM
雄激素受体(AR)通过促进G1-S进展在前列腺癌的发生和发展中起重要作用，可能通过作为DNA复制的许可因子发挥作用。我们报道了小剂量2-甲氧基雌二醇(2-ME)，一种内源性雌激素代谢产物，通过激活E3连接酶芯片(Hsp70相互作用蛋白的C末端)和AR的降解而诱导前列腺癌细胞有丝分裂停止。通过小干扰RNA(SiRNA)耗尽AR可以消除2-ME诱导的细胞分裂停滞，而将AR引入PC3-M细胞可以实现2-ME诱导的有丝分裂停滞。单独或联合敲除CHIP或MDM2(小鼠双分钟2蛋白同源物)可减少2-ME引起的AR降解和M期停滞。我们的数据将泛素化导致的AR退化与有丝分裂停滞联系在一起。通过激活E3连接酶如CHIP靶向AR代表了前列腺癌治疗的一种新策略。
The androgen receptor (AR) has a vital role in the onset and progression of prostate cancer by promoting G1-S progression, possibly by functioning as a licensing factor for DNA replication. We here report that low dose 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, induces mitotic arrest in prostate cancer cells involving activation of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein) and degradation of the AR. Depletion of the AR by small interfering RNA (siRNA) eliminates 2-ME-induced arrest and introducing AR into PC3-M cells confers 2-ME-induced mitotic arrest. Knockdown of CHIP or MDM2 (mouse homolog of double minute 2 protein) individually or in combination reduced AR degradation and abrogated M phase arrest induced by 2-ME. Our data link AR degradation via ubiquitination to mitotic arrest. Targeting the AR by activating E3 ligases such as CHIP represents a novel strategy for the treatment of prostate cancer.