Androgen receptor splice variants are resistant to inhibitors of Hsp90 and FKBP52, which alter androgen receptor activity and expression.
Androgen receptor splice variants are resistant to inhibitors of Hsp90 and FKBP52, which alter androgen receptor activity and expression.
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DOI：
10.1016/j.steroids.2012.12.013
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发表时间：
2013-06
期刊：
影响因子：
2.7
通讯作者：
Weigel NL
中科院分区：
文献类型：
--
作者：
Shafi AA;Cox MB;Weigel NL
雄激素消融疗法是晚期前列腺癌（PCa）最常见的治疗方法，但大多数患者会发展为去势抵抗性前列腺癌（CRPC），且无法治愈。 CRPC 具有雄激素耗竭抗性，但依赖于雄激素受体 (AR)。 AR 是一种核受体，其转录活性受到与配体结合域 (LBD) 结合的激素的调节。缺乏 LBD 的组成型活性 AR 剪接变体通常在 CRPC 中表达。这些变体的表达表明需要不依赖于灭活 LBD 来抑制 AR 活性的方法。热休克蛋白 90 (Hsp90) 是 PCa 的潜在治疗靶点，是 AR 伴侣，对于 AR 的正确折叠、激素结合和转录活性至关重要。我们生成了 AR-V7 变体表达受调节的 LNCaP 细胞系以及表达人工截短 AR 的细胞系（称为 AR-NTD）以表征剪接变体功能。使用 Hsp90 抑制剂格尔德霉素 (GA) 和 AR-Hsp90-FKBP52 特异性抑制剂 MJC13，我们试图确定 AR 变体是否也需要 Hsp90 和相关的辅助伴侣 FKBP52 来发挥其活性。 GA 抑制 AR 转录活性，但对 AR-V7 活性影响很小。此外，GA 降低了 AR 蛋白的稳定性，但对 AR-V7 水平没有影响。 MJC13 强烈抑制全长 AR 活性，而 AR-V7 不受影响。因此，这些变体对 Hsp90-AR 异质复合物的抑制剂具有抗性。尽管 Hsp90 抑制剂将继续抑制 CRPC 中的生长促进激酶和通过激活的全长 AR 的信号传导，但通过变体的 AR 信号传导将被保留。
Androgen ablation therapy is the most common treatment for advanced prostate cancer (PCa), but most patients will develop castration-resistant prostate cancer (CRPC), which has no cure. CRPC is androgen-depletion resistant but androgen receptor (AR) dependent. AR is a nuclear receptor whose transcriptional activity is regulated by hormone binding to the ligand-binding domain (LBD). Constitutively active AR splice variants that lack LBDs often are expressed in CRPC. The expression of these variants indicates that methods to inhibit AR activity that do not rely on inactivating the LBD are needed. Heat shock protein 90 (Hsp90), a potential therapeutic target in PCa, is an AR chaperone crucial for proper folding, hormone binding and transcriptional activity of AR. We generated LNCaP cell lines with regulated expression of the AR-V7 variant as well as a cell line expressing artificially truncated AR (termed AR-NTD) to characterize splice variant function. Using an Hsp90 inhibitor, Geldanamycin (GA), and an AR-Hsp90-FKBP52 specific inhibitor, MJC13, we sought to determine if the AR variants also require Hsp90 and associated co-chaperone, FKBP52, for their activity. GA inhibits AR transcriptional activity but has little effect on AR-V7 activity. Moreover, GA decreases the stability of AR protein, with no effect on AR-V7 levels. Full-length AR activity is strongly inhibited by MJC13 while AR-V7 is unaffected. Thus, the variants are resistant to inhibitors of the Hsp90-AR heterocomplex. Although Hsp90 inhibitors will continue to inhibit growth promoting kinases and signaling through activated full-length AR in CRPC, AR signaling through variants will be retained.
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影响因子：
10.9
作者：
Knudsen, Karen E.;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
影响因子：
11.2
作者：
Heemers HV;Schmidt LJ;Sun Z;Regan KM;Anderson SK;Duncan K;Wang D;Liu S;Ballman KV;Tindall DJ
通讯作者：
Tindall DJ
影响因子：
--
作者：
QUARMBY, VE;YARBROUGH, WG;WILSON, EM
通讯作者：
WILSON, EM
影响因子：
3.7
作者：
Zhang X;Morrissey C;Sun S;Ketchandji M;Nelson PS;True LD;Vakar-Lopez F;Vessella RL;Plymate SR
通讯作者：
Plymate SR
影响因子：
56.9
作者：
Tomlins, SA;Rhodes, DR;Chinnaiyan, AM
通讯作者：
Chinnaiyan, AM