Defining the role of PIM kinases in hypoxia-induced prostate cancer invasion

项目总结 预防前列腺癌的侵袭和转移仍然是降低前列腺癌死亡率的首要任务。 局部局限的肿瘤很少是致命的，在发生转移之前几乎可以保证存活，因此 了解入侵的驱动机制至关重要。一旦可能，司机是缺氧，或低 氧合作用。我们不知道缺氧驱动转移的生物学机制，目前 没有有效的治疗选择来预防它。然而，在这项研究提案中，我们有理由 认为低氧诱导的PIM通过调节ABI2而导致侵袭和转移增加 和肌动蛋白聚合。为了验证这一假设，我们将确定低氧如何调节ABI2水平和 WRC队形。为此，我们将研究低氧诱导的PIM磷酸化对Abi2的影响。 确定低氧和PIM对WRC的影响，并表征低氧对肌动蛋白动力学的影响。 此外，我们还将研究PIM在低氧诱导的侵袭中的作用。目标是确定是否 低氧诱导的PIM足以推动体外侵袭，并了解PIM在决定 体内细胞的侵袭潜能。这些数据应该有助于在PIM之间建立新的连接 低氧条件下细胞骨架重排对细胞运动的调节。阐明机制 调节运动性和侵袭性对于了解转移性疾病的进展至关重要。为了做到这一点 项目中，我们将建立一个新的前列腺特异性侵袭模型，以更好地概括人类 疾病。这将允许更好地了解转移过程，并最终应该提供对 如何提高患者的总体存活率。这些结果将阐明PIM的潜在治疗作用。 抑制剂以及如何使用它们来提高患者治疗的疗效。最后，这些数据还将 深入了解低氧如何增加侵袭性的机制，可在临床和 对病人的护理有直接影响。总而言之，拨款中建议的研究将阐明 缺氧是转移的驱动因素的机制，并提供了对以下途径的洞察 作为可行的药物靶点，在提高患者治疗效率的同时增加总体患者 生死存亡。

PROJECT SUMMARY The prevention of invasion and metastasis remains paramount for the reduction of prostate cancer mortality. Locally confined tumors are rarely lethal and survival is all but assured until metastasis occur, thus understanding the mechanisms driving invasion are critical. Once possible driver is hypoxia, or low oxygenation. We do not know the biological mechanisms by which hypoxia drives metastasis and currently have no effective therapeutic options to prevent it. However, in this research proposal, we have reason to believe that hypoxia-induced PIM is leading to increased invasion and metastasis through regulation of Abi2 and actin polymerization. To test this hypothesis, we will determine how hypoxia modulates Abi2 levels and WRC formation. To do this we will investigate the effects of hypoxia-induced PIM phosphorylation on Abi2, determine effects of hypoxia and PIM on the WRC, and characterize the effect of hypoxia on actin dynamics. Additionally, we will investigate the role of PIM in hypoxia-induced invasion. The goal is to determine whether hypoxia-induced PIM is sufficient to drive invasion in vitro and understand the role of PIM in determining invasive potential of cells in vivo. These data should help in establishing a novel connection between PIM kinases and regulation of cell motility via cytoskeletal rearrangement in hypoxia. Elucidating mechanisms regulating motility and invasion are critical for understanding metastatic disease progression. In doing this project, we will establish a novel prostate-specific invasion model to better recapitulate what occurs in human disease. This will allow for better clarity into the metastatic process and ultimately should provide insight into how to improve overall patient survival. These results will elucidate the potential therapeutic role for PIM inhibitors and how they could be used to increase the efficacy of patient treatment. Lastly these data will also yield insight into mechanisms of how hypoxia increases invasion that could be exploited in the clinic and make a direct impact on patients care. In summary, the research proposed in the grant will elucidate mechanisms by which hypoxia is a driving factor in metastasis and provide insight into pathways that serve as viable drug targets to improve efficacy of patient treatment while simultaneously increasing overall patient survival.