Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer.
Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer.
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DOI：
10.1158/1535-7163.mct-14-0819
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发表时间：
2015-03
影响因子：
5.7
通讯作者：
Nevalainen MT
中科院分区：
文献类型：
--
作者：
Hoang DT;Gu L;Liao Z;Shen F;Talati PG;Koptyra M;Tan SH;Ellsworth E;Gupta S;Montie H;Dagvadorj A;Savolainen S;Leiby B;Mirtti T;Merry DE;Nevalainen MT
尽管人们对雄激素受体(AR)信号知之甚少，但尽管前列腺癌接受了抗雄激素治疗，雄激素受体(AR)信号仍然持续存在，并且可能是不治之症的去势抵抗性前列腺癌发生的基础。然而，当前列腺癌进展到去势抵抗阶段时，针对AR信号轴的治疗最终会失败。Stat5a/b是前列腺癌的候选治疗靶蛋白，它与AR协同作用，相互增强两种蛋白的信号转导。在这项工作中，我们证明了Stat5a/b在前列腺癌细胞中隔离了抗雄激素配基(MDV3100，比卡鲁胺，氟他胺)AR，并保护它免受前列腺癌蛋白酶体的降解。激活的Stat5a/b增加了未连接和抗雄激素连接的AR的核水平，这在前列腺癌细胞系、异种移植瘤和临床患者来源的前列腺癌样本中得到了证实。在前列腺癌细胞中，Stat5a/b与AR之间的物理相互作用是由Stat5a/b的DNA结合域和AR的N端结构域共同介导的。此外，激活的Stat5a/b增加了前列腺特异性抗原启动子的AR占有率和AR调节的基因在前列腺癌细胞中的表达。从机制上讲，Stat5a/b基因敲除和抗雄激素治疗均可诱导前列腺癌细胞AR蛋白酶体降解，二者联合作用可导致AR蛋白的最大损失和前列腺癌细胞的存活。我们的结果表明，通过靶向Stat5a/b，使用抗雄激素治疗前列腺癌的AR靶向性可能会得到显著改善。
Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, Bicalutamide, Flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the Prostate Specific Antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b.