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

定义 PIM 激酶在缺氧诱导的前列腺癌侵袭中的作用

• 批准号: 10557063
• 负责人: Corbin C Jensen
• 金额: --
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-29 至 2023-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557063
• 关键词: 3-Dimensional; Actins; American; Antimetastatic Agent; Automobile Driving; Biochemical; Biological; Bladder; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Clinic; Clinical; Coculture Techniques; Complex; Cytoskeleton; Data; Detection; Disease; Disease Progression; Distant; Drops; Drug Targeting; Encapsulated; Genetic; Gland; Goals; Grant; Hypoxia; In Vitro; Indolent; Invaded; Knowledge; Link; Malignant neoplasm of prostate; Mediating; Mediator; Metastasis Induction; Modeling; Muscle; Nature; Neoplasm Metastasis; Oxygen; PIM1 gene; Pathway interactions; Patient Care; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Physiological; Polymers; Prevention; Progression-Free Survivals; Prostate; Proteins; Regulation; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Smooth Muscle; Survival Rate; Testing; Therapeutic; Translations; Treatment Efficacy; Tumor Cell Invasion; Tumor Promotion; Up-Regulation; Work; base; cancer cell; cancer diagnosis; cell motility; clinically relevant; human disease; hypoxia inducible factor 1; improved; in vivo; in vivo Model; inhibitor; innovation; insight; live cell imaging; male; men; metastatic process; mortality; neoplastic cell; novel; phosphoproteomics; polymerization; pre-clinical; predictive marker; prevent; prostate cancer metastasis; prostate cancer model; prostate cancer prevention; prostate cancer progression; proto-oncogene protein pim; therapeutically effective; treatment strategy; tumor; tumor growth; tumor progression

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.

项目摘要 预防侵袭和转移对于降低前列腺癌死亡率仍然至关重要。 局限于局部的肿瘤很少是致命的，并且在转移发生之前几乎可以保证生存，因此， 了解入侵的驱动机制是至关重要的。一旦可能的驱动程序是缺氧，或低 氧合我们不知道缺氧驱动转移的生物学机制， 没有有效的治疗方案来预防它。然而，在这项研究提案中，我们有理由 认为缺氧诱导的PIM通过调节Abi2导致侵袭和转移增加 和肌动蛋白聚合。为了验证这一假设，我们将确定缺氧如何调节Abi2水平， WRC阵型。为此，我们将研究缺氧诱导的PIM磷酸化对Abi2的影响， 确定缺氧和PIM对WRC的影响，并表征缺氧对肌动蛋白动力学的影响。 此外，我们将研究PIM在缺氧诱导的侵袭中的作用。目的是确定 缺氧诱导的PIM足以驱动体外侵袭，并了解PIM在决定细胞增殖中的作用。 细胞在体内的侵袭潜力。这些数据应该有助于在PIM之间建立一种新的连接 激酶和缺氧时通过细胞骨架重排调节细胞运动。阐明机制 调节运动性和侵袭性对于了解转移性疾病进展至关重要。这样做 项目，我们将建立一种新的前列腺特异性侵袭模型，以更好地概括人类中发生的情况 疾病这将使转移过程更清晰，并最终应提供洞察力， 如何提高患者的总体生存率。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功效。这些数据也将 深入了解缺氧如何增加侵袭的机制，可用于临床， 对患者的护理产生直接影响。总而言之，补助金中提出的研究将阐明 缺氧是转移的驱动因素的机制，并提供了对 作为可行的药物靶点，可提高患者治疗效果，同时增加总体患者 生存