Targeting Ribosomal Biogenesis in Prostate Cancer

项目总结/摘要：肥胖与高级别PC的更大风险相关， 治疗、转移和PC死亡。我们利用肥胖和攻击性PC之间的联系， 可操作的目标。为此，我们在肥胖小鼠中进行了靶向整个 kinome。如果激酶对肥胖宿主的生长至关重要，那么表达该shRNA的细胞亚群将 而不是生存。我们的筛选鉴定出了预期对肥胖宿主的生长至关重要的各种激酶， 胰岛素受体和胰岛素样生长因子1受体。我们的屏幕还识别出右开阅读 框架激酶2（RIOK 2）是一种关键的核糖体组装因子，在肥胖小鼠中是一种有前途的PC靶点， 表明核糖体生物合成在PC中起作用。 核糖体将mRNA翻译成蛋白质，并且在核仁中产生新的核糖体对于 增加癌细胞的生长速度。在PC中，增大或突出的核仁是一个标志 在原发性PC中，发现侵袭性PC和核糖体成分的表达上调，这是致癌基因的结果。 信号传导，或通过肿瘤抑制剂的丧失。我们确定致癌刺激也可以诱导核糖体 应激和促凋亡细胞周期阻滞，也称为由肿瘤抑制因子p53介导的核糖体应激检查点。 这个检查点的丢失释放了核糖体生物合成并加速了Myc驱动的淋巴瘤发生。 在PC中，雄激素受体（AR）和Myc癌基因也诱导核糖体生物合成，我们的初步研究表明， 数据表明，它们上调RIOK 2以维持细胞生长所需的高蛋白翻译速率， 师. RIOK 2对于新的核糖体组装至关重要，并确保核糖体在组装前完全发挥功能。 翻译mRNA以避免通过可能对PC细胞有害的专用监视途径降解。 事实上，RIOK 2缺失抑制蛋白质翻译并诱导多个PC细胞系中的细胞死亡， p53状态。这使我们假设PC癌基因Myc和AR增加核糖体 而靶向RIOK 2（一种关键的核糖体组装因子）的基因则中断了这一过程。 这是一种新的PC疗法。我们有一套独特的遗传小鼠模型， 通过核糖体应激检查点的丢失的不受限制的核糖体生物合成加速AR或Myc诱导的PC。 我们将评估AR和Myc诱导的蛋白翻译和PC细胞生长是否由RIOK 2介导， 确定在肥胖小鼠的PC异种移植物中用小分子抑制剂靶向RIOK 2的潜力。 通过PC癌基因增加的核糖体生物合成突出了潜在的治疗靶点。抑制核糖体 经由RIOK 2的生物发生在AR和Myc驱动的PC中是相关的，其为转移性PC的~70%。电流 正在研究的靶向核糖体合成的治疗策略依赖于功能性p53， 这是一个问题，因为超过50%的转移性PC具有突变或缺失的p53。完成这些 研究将为AR和/或Myc驱动的PC的新疗法提供理论依据，而不管p53状态如何。

PROJECT SUMMARY/ABSTRACT: Obesity is linked with greater risk of high-grade PC, recurrence after therapy, metastases, and PC death. We exploited the link between obesity and aggressive PC to identify actionable targets. To this end, we performed a shRNA genomic screen in obese mice targeting the entire kinome. If kinase is essential for growth in obese hosts the subpopulation of cells expressing that shRNA will not survive. Our screen identified various kinases expected to be essential for growth in obese host such as insulin receptor and insulin like growth factor 1 receptor. Our screen also indentified Right Open Reading Frame Kinase 2 (RIOK2), a key ribosome assembly factor, as a promising PC target in obese mice and suggests that ribosomal biogenesis plays a role in PC. Ribosomes translate mRNA to protein and production of new ribosomes in the nucleolus is essential for increased for increased growth rates of cancer cells. In PC, enlargement or prominent nucleoli are a hallmark of invasive PC and ribosome components are found upregulated in primary PCs as the result of oncogenic signaling, or by loss of tumor suppressors. We established that oncogenic stimuli can also induce ribosomal stress and elicits cell cycle arrest a.k.a ribosomal stress checkpoint mediated by the tumor suppressor p53. Loss of this checkpoint unleashed ribosomal biogenesis and accelerated Myc-driven lymphomagenesis. In PC, Androgen Receptor (AR) and Myc oncogenes also induce ribosomal biogenesis and our preliminary data suggest they upregulate RIOK2 to maintain high rates of protein translation needed cell growth and division. RIOK2 is critical for new ribosome assembly and ensures ribosomes are fully functional before translating mRNA to avoid degradation by dedicated surveillance pathways which could be harmful to PC cells. In fact, RIOK2 loss inhibits protein translation and induces cell death in multiple PC cell lines independent of p53 status. This led us to hypothesize that the PC oncogenes Myc and AR increase ribosome biogenesis for PC growth, and that targeting RIOK2, a key ribosomal assembly factor, interrupts this process leading to a novel PC therapy. We have a unique set of genetic mouse models to assess if unrestricted ribosomal biogenesis via loss of ribosomal stress checkpoint accelerates AR or Myc-induced PC. We will evaluate if AR and Myc induced protein translation and PC cell growth are mediated by RIOK2 and determine the potential of targeting RIOK2 with small molecule inhibitors in PC xenografts in obese mice. Increased ribosomal biogenesis by PC oncogenes highlights a potential therapeutic target. Inhibiting ribosome biogenesis via RIOK2 would be relevant in AR and Myc driven PCs, which is ~70% of metastatic PCs. Current therapuetic strategies under investigation to target ribosome synthesis rely on functional p53, which is problematic since upwards of 50% of metastatic PCs have a mutated or deleted p53. Completion of these studies would provide a rationale for a new therapy in AR and/or Myc-driven PCs irrespective of p53 status.