The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway
The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway
复制标题
TXNDC5在去势抵抗性前列腺癌中的作用——涉及雄激素受体信号通路
DOI：
10.1038/onc.2014.401
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发表时间：
2015-09-03
期刊：
影响因子：
8
通讯作者：
Han, B.
中科院分区：
文献类型：
--
作者：
Wang, L.;Song, G.;Han, B.
去势抵抗性前列腺癌（CRPC）仍然是一个主要的临床问题，其背后的机制仍不清楚。含硫氧还蛋白结构域蛋白5（TXNDC 5）参与蛋白质折叠和伴侣活性，其过表达已在多种恶性肿瘤中报道。在目前的研究中，我们证明了TXNDC 5在长期雄激素剥夺治疗（ADT）后上调，并且与未经治疗的前列腺癌（PCa）病例相比，在CRPC肿瘤中高度过表达。在功能上，体外和体内研究表明，TXNDC 5过表达促进雄激素依赖性和去势抵抗性PCa异种移植物的生长。在机制上，TXNDC 5直接与AR蛋白相互作用以增加其稳定性，从而增强其转录活性。TXDNC 5介导的CRPC生长可以通过AR抑制完全消除，表明TXDNC 5上调是低雄激素环境中异常AR再激活和CRPC生长的逃逸途径。事实上，我们发现TXNDC 5通过ADT诱导的缺氧通过HIF-1 α以miR-200 b依赖性方式增加。总之，我们确定了TXNDC 5在CRPC中的重要作用，需要进一步研究筛选TXNDC 5拮抗剂作为治疗PCa患者CRPC的新治疗方法。
Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and the mechanisms behind it remain unclear. Thioredoxin domain-containing protein 5 (TXNDC5) is involved in protein folding and chaperone activity, and its overexpression has been reported in multiple malignancies. In the current study, we demonstrated that TXNDC5 is up-regulated following long-term androgen-deprivation treatment (ADT) and is highly overexpressed in CRPC tumors compared with hormone-naive prostate cancer (PCa) cases. Functionally, in vitro and in vivo studies demonstrated that TXNDC5 overexpression promotes the growth of both androgen-dependent and castration-resistant PCa xenografts. Mechanistically, TXNDC5 directly interacts with the AR protein to increase its stability and thus enhances its transcriptional activity. TXDNC5-mediated CRPC growth can be fully abolished by AR inhibition, suggesting TXDNC5 up-regulation as an escape pathway for aberrant AR re-activation and CRPC growth in the milieu of low androgen. Indeed, we found that TXNDC5 is increased by ADT-induced hypoxia through HIF-1 alpha in an miR-200b-dependent manner. Overall, we defined an important role of TXNDC5 in CRPC and further investigations are needed to screen TXNDC5 antagonists as a novel therapeutic approaches to treat PCa patients with CRPC.