Offermann Anne, Vlasic Ignacija, Syring Isabella, Vogel Wenzel, Ruiz Christian, Zellweger Tobias, Rentsch Cyrill A, Hagedorn Susanne, Behrends Jochen, Nowak Michael, Merseburger Axel, Bubendorf Lukas, Kirfel Jutta, Duensing Stefan, Adler David, Perner Sven
Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
Department of Urology, University Hospital Bonn, Bonn, Germany.
Oncotarget. 2017 Jan 31;8(5):7964-7976. doi: 10.18632/oncotarget.13860.
Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%. A validation cohort comprising samples before and after therapy confirmed our observations. Protein analysis for pAKT and pSMAD3 shows that MED15 correlates with PI3K and TGFß activities, respectively, and that hyper-activation of both pathways simultaneously correlates with highest levels of MED15. We further show that MED15 protein expression increases in LNCaP cells under androgen deprivation, and via EGF mediated PI3K activation. PI3K/mTOR and TGFß-receptor inhibition results in decreased MED15 expression. MED15 knockdown reduces LNCaP cell viability and induces apoptosis during androgen deprivation, while cell cycle is not affected. Collectively, MED15 overexpression arises during ADT via hyper-activation of PI3K/mTOR signaling, thus MED15 may serve as a predictive marker for response to PI3K/mTOR inhibitors. Furthermore, MED15 is potentially a therapeutic target for the treatment of CRPC.
雄激素剥夺疗法（ADT）是晚期前列腺癌（PCa）的主要治疗选择。在初始消退后，大多数肿瘤会发展为去势抵抗性前列腺癌（CRPC）。此前，我们发现中介体复合物亚基MED15在CRPC中过表达，并与临床结果相关。因此，我们研究了MED15是否参与了向CRPC进展过程中发生的信号变化。对同一患者ADT前后的匹配样本进行MED15免疫组织化学（IHC）分析发现，72%的患者在ADT后MED15表达显著增加。一个包含治疗前后样本的验证队列证实了我们的观察结果。对pAKT和pSMAD3的蛋白质分析表明，MED15分别与PI3K和TGFβ活性相关，并且这两条通路的同时过度激活与MED15的最高水平相关。我们进一步表明，在雄激素剥夺条件下，LNCaP细胞中MED15蛋白表达增加，并且是通过EGF介导的PI3K激活实现的。PI3K/mTOR和TGFβ受体抑制导致MED15表达降低。MED15基因敲低会降低LNCaP细胞活力，并在雄激素剥夺期间诱导细胞凋亡，而细胞周期不受影响。总体而言，MED15的过表达在ADT期间通过PI3K/mTOR信号的过度激活而出现，因此MED15可能作为对PI /mTOR抑制剂反应的预测标志物。此外，MED15可能是治疗CRPC的一个治疗靶点。
