Androgen Receptor Splice Variants Determine Taxane Sensitivity in Prostate Cancer
Androgen Receptor Splice Variants Determine Taxane Sensitivity in Prostate Cancer
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DOI：
10.1158/0008-5472.can-13-2876
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发表时间：
2014-04-15
期刊：
影响因子：
11.2
通讯作者：
Giannakakou, Paraskevi
中科院分区：
文献类型：
--
作者：
Thadani-Mulero, Maria;Portella, Luigi;Giannakakou, Paraskevi
前列腺癌的生长依赖于雄激素受体信号。雄激素消融治疗诱导组成活性雄激素受体剪接变异体的表达，从而推动疾病进展。紫杉烷是去势抵抗性前列腺癌（CRPC）的标准护理治疗；然而，紫杉烷的临床活性机制尚不清楚。最近的研究表明，前列腺细胞的微管网络对雄激素受体核易位和活性至关重要。在本研究中，我们使用了一组雄激素受体缺失突变体来鉴定雄激素受体的微管结合域，包括DNA结合域和铰链区。我们报道了两个临床相关的雄激素受体剪接变体ARv567和ARv7与微管和动力蛋白运动蛋白的不同关联，从而导致体外和体内紫杉烷敏感性的差异。与ARv567不同，缺乏铰链区的ARv7不与微管共沉淀，也不与动力蛋白共沉淀。机制研究表明，ARv7的核积累和转录活性不受紫杉烷处理的影响。相比之下，微管相互作用剪接变体ARv567对紫杉烷诱导的微管稳定敏感。在表达arv567的LuCap86.2肿瘤异种移植物中，多西他赛治疗非常有效，而表达arv7的LuCap23.1肿瘤异种移植物则表现出多西他赛耐药性。我们的研究结果表明，在CRPC细胞中积累的雄激素受体变异利用不同的核输入途径影响紫杉烷的抗肿瘤功效，这表明为CRPC患者定制治疗的机制原理，这可能会改善结果。(c) 2014年aacr。
Prostate cancer growth depends on androgen receptor signaling. Androgen ablation therapy induces expression of constitutively active androgen receptor splice variants that drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC); however, mechanisms underlying the clinical activity of taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for androgen receptor nuclear translocation and activity. In this study, we used a set of androgen receptor deletion mutants to identify the microtubule-binding domain of the androgen receptor, which encompasses the DNA binding domain plus hinge region. We report that two clinically relevant androgen receptor splice variants, ARv567 and ARv7, differentially associate with microtubules and dynein motor protein, thereby resulting in differential taxane sensitivity in vitro and in vivo. ARv7, which lacks the hinge region, did not co-sediment with microtubules or coprecipitate with dynein motor protein, unlike ARv567. Mechanistic investigations revealed that the nuclear accumulation and transcriptional activity of ARv7 was unaffected by taxane treatment. In contrast, the microtubule-interacting splice variant ARv567 was sensitive to taxane-induced microtubule stabilization. In ARv567-expressing LuCap86.2 tumor xenografts, docetaxel treatment was highly efficacious, whereas ARv7-expressing LuCap23.1 tumor xenografts displayed docetaxel resistance. Our results suggest that androgen receptor variants that accumulate in CRPC cells utilize distinct pathways of nuclear import that affect the antitumor efficacy of taxanes, suggesting a mechanistic rationale to customize treatments for patients with CRPC, which might improve outcomes. (C) 2014 AACR.