Prolonged Treatment With Bicalutamide Induces Androgen Receptor Overexpression and Androgen Hypersensitivity
Prolonged Treatment With Bicalutamide Induces Androgen Receptor Overexpression and Androgen Hypersensitivity
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DOI：
10.1002/pros.21107
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发表时间：
2010-05-15
期刊：
影响因子：
2.8
通讯作者：
Aoki, Yuko
中科院分区：
文献类型：
--
作者：
Kawata, Hiromitsu;Ishikura, Nobuyuki;Aoki, Yuko
背景。已经建立了具有雄激素耗竭的各种激素难治性前列腺癌细胞模型，并有助于阐明向雄激素耗竭独立状态转变的机制。然而，由于细胞模型很少，比卡鲁胺耐药的机制仍不清楚。方法。经过比卡鲁胺长期治疗后，我们从 LNCaP 中产生了比卡鲁胺耐药亚系 LNCaP-BC2。在体外和体内检查了雄激素和/或比卡鲁胺对增殖和前列腺特异性抗原（PSA）分泌的反应性。通过液相色谱-串联质谱法分析异种移植肿瘤中的睾酮和二氢睾酮（DHT）水平。测定雄激素受体(AR)基因突变和扩增以及AR和pAR(210)的表达。结果。 LNCaP-BC2 不在雄激素耗尽的培养基中生长，并且在比 LNCa P 低十倍的雄激素浓度下刺激增殖。LNCaP-BC2 在去势雄性小鼠中生长，移植的 LNCaP-BC2 肿瘤中的 DHT 水平比 LNCaP 肿瘤中的 DHT 水平低 7.7 倍。比卡鲁胺体外刺激LNCaP-BC2增殖和PSA分泌，体内比卡鲁胺对LNCaP-BC2的抗肿瘤活性弱于LNCaP。 LNCaP-BC2 中未检测到额外的 AR 突变和 AR 基因扩增，但 LNCaP-BC2 中的 AR 和 pAR(210) 表达以及 PSA 分泌量高于 LNCaP。结论。比卡鲁胺耐药的 LNCaP-BC2 表现出 AR 过度表达和对低水平雄激素过敏。我们的数据表明，AR 过度表达是比卡鲁胺耐药的一个重要机制，类似于慢性雄激素耗竭的耐药。此外，pAR(210)过表达可能是LNCaP-BC2对低雄激素过敏的潜在机制。前列腺 70：745-754，2010。(C) 2010 Wiley-Liss, Inc.
BACKGROUND. Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status. However, the mechanism of bicalutamide resistance remains unclear because few cell models have been generated.METHODS. We generated a bicalutamide-resistant subline, LNCaP-BC2, from LNCaP after prolonged treatment with bicalutamide. Androgen and /or bicalutamide responsiveness for proliferation and prostate-specific antigen (PSA) secretion were examined in vitro and in vivo. Testosterone and dihydrotestosterone (DHT) levels in xenografted tumors were analyzed by liquid chromatography-tandem mass spectrometry. Androgen receptor (AR) gene mutation and amplification and AR and pAR(210) expression were determined.RESULTS. LNCaP-BC2 did not grow in an androgen-depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCa P. LNCaP-BC2 grew in castrated male mice, and the DHT level in grafted LNCaP-BC2 tumors was 7.7-fold lower than in LNCaP tumors. Bicalutamide stimulated LNCaP-BC2 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP-BC2 was weaker than that of LNCaP in vivo. Additional AR mutation and AR gene amplification were not detected in LNCaP-BC2, but AR and pAR(210) expression and PSA secretion in LNCaP-BC2 were higher than in LNCaP.CONCLUSIONS. Bicalutamide-resistant LNCaP-BC2 exhibited AR overexpression and hypersensitivity to low levels of androgen. Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion. In addition, pAR(210) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP-BC2. Prostate 70: 745-754, 2010. (C) 2010 Wiley-Liss, Inc.