Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536.
Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47907; Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907.
J Biol Chem. 2020 Apr 17;295(16):5470-5483. doi: 10.1074/jbc.RA119.011385. Epub 2020 Mar 17.
Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both and Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.
前列腺癌（PCa）细胞严重依赖活跃的雄激素受体（AR）通路来存活。恩扎卢胺（MDV3100）是第二代抗雄激素药物，于 2012 年被美国食品和药物管理局批准用于治疗去势抵抗性前列腺癌（CRPC）患者。然而，对这种药物的耐药性的出现是不可避免的，开发有助于管理恩扎卢胺耐药性 CRPC 的干预措施一直是一个主要挑战。促红细胞生成素产生的人肝细胞（Eph）受体被 Ephrin 蛋白配体靶向，具有广泛的功能。越来越多的证据表明，该信号通路在肿瘤发生中起着重要作用。EPH 受体 B4（EPHB4）的过表达已在多种类型的癌症中观察到，与肿瘤的增殖、侵袭和转移密切相关。在这里，我们使用临床和临床前样本的 RNA-Seq 分析以及几种生化和分子方法，报告恩扎卢胺耐药性 PCa 需要一个活跃的 EPHB4 通路，该通路支持这种肿瘤类型的耐药性。使用小激酶抑制剂和基于 RNAi 的基因沉默来破坏 EPHB4 活性，我们发现这些破坏使恩扎卢胺耐药性 PCa 对药物重新敏感， 和 。从机制上讲，我们发现 EPHB4 通过诱导原癌基因 c-Myc（c-Myc）表达来刺激 AR。总之，这些结果为 PCa 中恩扎卢胺耐药的机制提供了重要的见解，可能为增强恩扎卢胺的疗效提供了一种治疗途径，以更好地管理这种常见的恶性肿瘤。
