Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer.
Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer.
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靶向蛋白酶体相关去泛素酶作为治疗雌激素受体阳性乳腺癌的新策略
DOI：
10.1038/s41389-018-0086-y
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发表时间：
2018-09-24
期刊：
影响因子：
6.2
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Xia X;Liao Y;Guo Z;Li Y;Jiang L;Zhang F;Huang C;Liu Y;Wang X;Liu N;Liu J;Huang H
雌激素受体α(ERα)在67%的乳腺癌中表达，对乳腺癌的增殖和发展起关键作用。ERα的表达被认为是一个重要的预后指标，使其成为乳腺癌治疗的有意义的靶点。然而，激素受体阳性的BCA有时对经典的抗激素疗法(如氟维斯特兰和他莫昔芬)没有反应，甚至耐药。因此，对于ERα+BCA，迫切需要新的抗内分泌治疗。一项II期研究表明，Bortezomib是一种阻断20 S蛋白酶体活性的抑制剂，它干预了BCA的抗内分泌治疗的癌症进展。在这里，我们报告了蛋白酶体相关脱泛素酶(USP14和UCHL5)抑制剂b-AP15和铂吡硫酮(PtPT)对ERα+Bca细胞的生长抑制作用。进一步的研究表明，这些抑制剂诱导细胞周期停滞和凋亡与caspase激活、内质网(ER)应激和ERα下调有关。此外，我们认为b-AP15和PtPT通过促进泛素介导的ERα的降解和抑制ERα的转录来阻断ERα信号转导。总而言之，这些发现表明，蛋白酶体相关的脱泛素酶抑制剂b-AP15和PtPT可能具有治疗抗激素治疗耐药的BCA的潜力。
Estrogen receptor α (ERα) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERα is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ERα+ BCa. A phase II study suggested that bortezomib, an inhibitor blocking the activity of 20 S proteasomes, intervenes in cancer progression for anti-endocrine therapy in BCa. Here we report that proteasome-associated deubiquitinases (USP14 and UCHL5) inhibitors b-AP15 and platinum pyrithione (PtPT) induce growth inhibition in ERα+ BCa cells. Further studies show that these inhibitors induce cell cycle arrest and apoptosis associated with caspase activation, endoplasmic reticulum (ER) stress and the downregulation of ERα. Moreover, we suggest that b-AP15 and PtPT block ERα signaling via enhancing the ubiquitin-mediated degradation of ERα and inhibiting the transcription of ERα. Collectively, these findings demonstrate that proteasome-associated deubiquitinases inhibitors b-AP15 and PtPT may have the potential to treat BCa resistant to anti-hormonal therapy.
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