Androgen Deprivation Activates Wnt/Beta-Catenin Signaling in Prostate Cancer

摘要 雄激素剥夺疗法已成为治疗晚期前列腺癌的金标准。 癌症(PCA)自20世纪60年代以来一直存在。患者最初对导致肿瘤消退的治疗反应良好，但 最终发展为抗去势的PCA，目前还没有治愈的方法。新的抗雄激素药物已经显示出 对雄激素剥夺治疗失败的前列腺癌患者的治疗有显著改善。然而，即使是PCA 服用苯扎鲁胺(最有效的抗雄激素疗法)的患者最终进展为对去势耐受 PCA。此外，一旦PCA变得对去势具有抵抗力，就会出现侵袭性的神经内分泌(NE)表型 发病率高，平均生存期不到1.5年。目前还没有有效的 对NE表型突出的前列腺癌的治疗。因此，通过确定机制(S) 抗雄激素治疗的结果是哪种NE表型对新药的开发至关重要 针对前列腺癌的治疗。Wnt/β-catenin信号通路在晚期PCa中广泛存在。我们 以往的研究表明，Wnt/β-catenin信号通路的激活促进了去势的发生。 具有NE表型增加的抗性PCA，从而将活跃的Wnt/β-catenin信号与 去势抵抗进展和去甲肾上腺素在前列腺癌中的出现。与此一致的是，我们 证实了Wnt/β-catenin途径在NEPCa中是活跃的。雄激素缺乏一直是 表明促进了前列腺癌中NE表型的出现。我们的初步数据表明 雄激素剥夺使Wnt7a表达上调，Wnt7a是一种Wnt配体，可以激活Wnt/β-catenin信号。我们的数据 也表明，雄激素剥夺上调了Dkk1，一种内源性Wnt/β-分泌抑制因子。 连环蛋白信号在正常前列腺中表达，但在前列腺癌中不表达。基于这些观察，我们假设 雄激素剥夺激活Wnt/β-catenin信号促进去势抵抗进展和去甲肾上腺素 主成分分析的辨证。这一假设将通过以下具体目标进行检验：目标1：确定如何 雄激素剥夺可激活PCa中的Wnt/β-catenin信号。目的2：确定发病机制(S) 雄激素剥夺通过调节间质/上皮调节Wnt/β-catenin信号转导 互动。目的3：确定是否阻断Wnt/β-连环蛋白途径(通过诱导表达 Dkk1和药物抑制剂)抑制NEPCA。

SUMMARY Androgen deprivation therapy has been the gold standard for the treatment of advanced prostate cancer (PCa) since the 1960s. Patients initially respond well to the treatment resulting in tumor regression, but ultimately progress to castrate-resistant PCa for which there is no cure. New anti-androgens have shown significant improvement in treating PCa patients who failed androgen deprivation therapy. However, even PCa patients on enzalutamide (the most potent anti-androgen therapy), eventually progress to castrate-resistant PCa. Moreover, once PCa becomes castrate-resistant, an aggressive neuroendocrine (NE) phenotype ensue with high morbidity, with only an average survival of less than 1.5 years. There are currently no effective treatments against PCa with a prominent NE phenotype. Therefore, identifying the mechanism(s) through which NE phenotype arises as consequence to anti-androgen therapies is critical for the development of novel therapeutics against PCa. The Wnt/beta-Catenin signaling pathway is prevalent in advanced PCa. We previously showed that activation of Wnt/beta-Catenin signaling promotes the development of castrate- resistant PCa with an increased NE phenotype, thus linking the active Wnt/beta-Catenin signaling with castrate-resistant progression and the emergence of NE phenotype in PCa. Consistent with this, we corroborated that the Wnt/beta-Catenin pathway is active in the NEPCa. Androgen deprivation has been shown to accelerate the emergence of the NE phenotype in PCa. Our preliminary data demonstrated that androgen deprivation upregulated Wnt7a, a Wnt ligand that can activate Wnt/beta-Catenin signaling. Our data also indicated that androgen deprivation upregulated Dkk1, an endogenous secretory inhibitor of the Wnt/beta- Catenin signaling, in normal prostates but not in PCa. Based on these observations, we hypothesize that androgen deprivation activates Wnt/beta-Catenin signaling to promote castrate-resistant progression and NE differentiation of PCa. This hypothesis will be tested by the following Specific Aims: Aim 1: To determine how androgen deprivation activates Wnt/beta-Catenin signaling in PCa. Aim 2: To determine the mechanism(s) through which androgen deprivation modulates Wnt/beta-Catenin signaling by regulating stromal/epithelial interaction. Aim 3: To determine whether blocking the Wnt/beta-Catenin pathway (via inducible expression of DKK1 and pharmacological inhibitors) suppresses NEPCa.