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

总结 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 非裔美国人前列腺癌的死亡率是白人的2.44倍。 已经开发了诸如手术、放射和雄激素消融的疗法来控制PCa患者， 不同的阶段然而，在许多情况下报告了这种疾病的复发，特别是在 晚期转移，最终患者死于去势复发性生长 耐药前列腺癌（CRPC）。研究表明，肿瘤抑制因子和 癌基因有助于PCa的发生和进展以及CRPC的复发性生长。新兴 有证据表明CRPC生长是一种复杂的恶性肿瘤， 途径。导致CRPC的致癌信号通路的机制知之甚少， 异常激活以背景和环境依赖性方式调节。然而，迫切需要探索 因此，我们需要开发新的药物，并进一步开发有效的治疗方法，以降低PCa的发病率和死亡率 消除各民族之间的差距。SKP 2和AR的异常升高是常见的 晚期PCa和CRPC。我们发现SKP 2失活部分抑制PCa进展， 还导致AR和FOXA 1通路的异常升高。我们假设AR海拔的升高 在前列腺癌细胞中对SKP 2抑制的抗性以及SKP 2和AR的联合抑制可以有效地 抑制CRPC的增长。我们建议通过评估以下基因的分子谱来验证这一假设： SKP 2对FOXA 1/AR的调控及其与AR联合靶向对PCa细胞增殖的影响 以及其联合治疗对体内小鼠前列腺肿瘤的抑制效果。以下 具体目标如下：1）明确SKP 2对FOXA 1/AR通路的调控机制， PCa细胞; 2）研究PCa细胞中SKP 2对FOXA 1/AR信号传导的分子谱;和3）研究PCa细胞中SKP 2对FOXA 1/AR信号传导的影响。 SKP 2和AR抑制的组合靶向对体内PCa进展的抑制的功效。结果 将提供一种新的和有效的治疗方案来抑制CRPC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.