Estrogen receptor-β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated
Estrogen receptor-β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated
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DOI：
10.1073/pnas.0905524107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Risbridger, Gail P.
中科院分区：
文献类型：
--
作者：
McPherson, Stephen J.;Hussain, Shirin;Risbridger, Gail P.
前列腺癌（PCa）和良性前列腺增生（BPH）是雄激素依赖性疾病，通常通过抑制雄激素作用来治疗。然而，雄激素消除或去势未能针对与疾病病因和复发有关的雄激素非依赖性细胞。与去势机制不同，这项研究表明雌激素受体 β (ER β) 对 BPH 和 PCa 具有有益的促凋亡作用。 ER β 激动剂可诱导缺乏雌激素的芳香酶敲除小鼠的前列腺基质细胞、管腔细胞和去势抵抗性基底上皮细胞凋亡。这是通过外源性（caspase-8）途径发生的，不会减少血清激素，并扰乱上皮的再生能力。 TNF α 敲除小鼠无法对 ER β 激动剂产生反应，这证明了 TNF α 信号传导的需要。在人体组织中，ER β 激动剂诱导异种移植 BPH 标本的基质和上皮细胞凋亡，包括体外从 BPH-1 细胞分离的富含 CD133(+) 的推定干细胞/祖细胞。在 PCa 中，ER beta 通过 caspase-8 引起格里森 7 级异种移植组织和雄激素非依赖性细胞系（PC3 和 DU145）细胞凋亡。这些数据提供了 ER β 激动剂对 BPH 的上皮和基质以及与复发性疾病有关的不依赖雄激素的肿瘤细胞的有益作用的证据。我们的数据表明 ER β 激动剂在治疗 PCa 和/或 BPH（伴或不伴雄激素戒断）方面具有治疗潜力。
Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor-beta (ER beta) in BPH and PCa. ER beta agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNF alpha knock-out mice fail to respond to ER beta agonist, demonstrating the requirement for TNFa signaling. In human tissues, ER beta agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133(+) enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ER beta causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ER beta agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ER beta agonist for treatment of PCa and/or BPH with or without androgen withdrawal.