Novel mechanisms of SKP2 and AR signaling on the suppression of prostate cancer

摘要 前列腺癌(PCA)是美国男性癌症相关死亡的第二大原因。发病率 非裔美国人的前列腺癌死亡率是高加索人的2.44倍。 已经开发出手术、放射和雄激素消融等治疗方法来控制患者的前列腺癌 不同的阶段。然而，这种疾病的复发在许多情况下都有报道，特别是在 晚期-转移，结果患者最终死于去势的复发性生长 耐药前列腺癌(CRPC)。研究表明肿瘤抑制因子和肿瘤抑制因子的各种变化 癌基因参与了PCa的发生、发展以及CRPC的复发生长。新兴 有证据表明，CRPC的生长是一种复杂的恶性肿瘤，具有多种致癌基因的失调。 小路。导致CRPC的致癌信号通路的机制尚不清楚，其 异常激活是以上下文和环境相关的方式调节的。然而，迫切需要探索的是 开发新的药物，进一步开发有效的治疗方法，以降低前列腺癌的发生率和死亡率 消除各民族之间的差距。Skp2和AR的异常升高是常见的 在高级PCA和CRPC中。我们发现Skp2失活部分抑制了前列腺癌的进展，但 也会导致AR和FOXA1通路的异常抬高。我们假设AR Elevation赋予 前列腺癌对Skp2抑制的抵抗和Skp2和AR的联合抑制可以有效地 抑制CRPC的增长。我们建议通过评估分子图谱来检验这一假说 Skp2调控的FOXA1/AR联合靶向Skp2和AR对体外培养的PCa细胞的抗增殖作用 及其联合治疗对小鼠体内前列腺癌的抑制作用。以下是 具体目标是：1)明确Skp2对FOXA1/AR信号通路的调控机制 2)研究Skp2在PCa细胞中对FOXA1/AR信号的分子表达；以及3)研究FOXA1/AR信号在PCa细胞中的表达。 联合靶向Skp2和AR抑制对体内前列腺癌进展的抑制作用结果 将提供一种新的有效的治疗方案来抑制CRPC的生长。

SUMMARY Prostate Cancer (PCa) is the second-leading cause of cancer-related deaths in American men. The morbidity and the mortality to PCa are 2.44-fold higher in African American men as compared to Caucasian counterparts. Therapies such as surgery, radiation and androgen-ablation have been developed to control PCa for patients at different stages. However, the relapse of this disease is reported in many cases, particularly in patients at advanced stage-metastasis, and as a result patients eventually died of the recurrent growth of castration resistant prostate cancer (CRPC). Studies demonstrated that various alterations of tumor suppressors and oncogenes contribute to the initiation and progression of PCa as well as the recurrent growth of CRPC. Emerging evidence revealed that CRPC growth is a complicated malignancy with dysregulation of multiple oncogenic pathways. Mechanisms on the oncogenic signaling pathways leading to CRPC are poorly understood, and their aberrant activations are regulated in a context and environment dependent manner. Yet, it is urgent to explore novel drugs and further to develop efficient treatments in order to reduce the incidence and mortality rate of PCa and to eliminate the disparities among ethnic groups. Aberrant elevation of SKP2 and AR are frequently found in advanced PCa and CRPC. We discovered that SKP2 inactivation partially suppresses PCa progression but also leads to aberrant elevation of AR and FOXA1 pathways. We HYPOTHESIZE that AR elevation confers resistance to SKP2 inhibition in prostate cancer cells and a combined inhibition of SKP2 and AR can effectively suppress the CRPC growth. We propose to test this hypothesis by evaluating the molecular profiling of FOXA1/AR regulated by SKP2, the anti-proliferation effects of co-targeting SKP2 and AR in PCa cells in vitro and its efficacy of combined treatment on the suppression of prostate tumors in mice in vivo. The following specific aims are proposed: 1) Define the mechanisms on the regulation of FOXA1/AR pathways by SKP2 in PCa cells; 2) Study the molecular profiling of FOXA1/AR signaling by SKP2 in PCa cells; and 3) Investigate the efficacy of combined targeting of SKP2 and AR inhibition on the suppression of PCa progression in vivo. Results will provide a novel and efficient therapeutic regimen to suppress CRPC growth.