Mitochondrial Redox Control of Metastasis

线粒体氧化还原对转移的控制

• 批准号: 8525758
• 负责人: Nadine Hempel
• 金额: $ 24.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525758
• 关键词: Actins; Address; Adjuvant Therapy; Affect; Antioxidants; Behavior; Cancer Model; Cancer cell line; Cells; Cytosol; DNA Sequence Rearrangement; Data; Development; Disseminated Malignant Neoplasm; Distant; Effectiveness; Event; Excision; Focal Adhesion Kinase 1; Focal Adhesions; Human; Hydrogen Peroxide; Immigration; In Vitro; Invaded; Knowledge; Lead; Malignant neoplasm of urinary bladder; Mediator of activation protein; Membrane; Mitochondria; Modeling; Molecular; Movement; Neoplasm Metastasis; Oxidation-Reduction; PTEN gene; PTEN protein; Phenotype; Phosphatidylinositols; Phospholipids; Phosphoric Monoester Hydrolases; Phosphorylation; Primary Neoplasm; Production; Protein Tyrosine Phosphatase; Proteins; Reactive Oxygen Species; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Site; Spatial Distribution; Staging; Testing; Therapeutic; Tumor Cell Invasion; Tumorigenicity; Tyrosine; base; cancer cell; cancer therapy; cancer type; catalase; human BCAR1 protein; in vivo; in vivo Model; migration; neoplastic cell; novel; oxidation; phosphoinositide-3,4,5-triphosphate; second messenger; tumor progression; tumorigenic

Movement of cancer cells from the primary tumor to distant metastatic sites represents the most lethal stage of cancer progression. The potential for a cell to migrate and invade depends on a multitude of signaling pathways, which present novel targets for anti-cancer therapies. Reactive Oxygen Species (ROS) are known modulators of tumorigenicity and act as novel second messengers in a multitude of cellular signaling cascades. Intrinsic levels of ROS are elevated in numerous metastatic cancer types. The ability of tumor cells to survive and thrive with an increased ROS milieu suggests that these have evolved to utilize changes in sublethal ROS levels to drive pro-metastatic signaling events. Our preliminary data suggest that picomolar sublethal increases in mitochondrial derived ROS/hydrogen peroxide (H2O2) lead to a more tumorigenic, migratory and invasive phenotype in metastatic cancer cells, in vitro and in vivo. These changes in ROS lead to alterations in pro-migratory signaling cascades, following oxidation and inactivation of key phosphatases. In addition, these studies present a novel concept that H2O2 is a regulatory factor that essentially has opposing effects on membrane localization of pro- and anti- migratory signaling players. We therefore hypothesize that sub lethal increases in mitochondrial ROS production regulate the spatial activation of pro-migratory signaling pathways enhancing the metastatic potential of cancer cells. Using a metastatic bladder cancer model this will be tested by: 1) Investigating the cellular site of action of mitochondrial ROS and their role in regulating oxidation and spatial distribution of Protein Tyrosine Phosphatases (PTPs) involved in migratory signaling. 2) Determining the effects of mitochondrial ROS on mediators of Focal Adhesion Kinase signaling during migration; and 3) Assessing the consequences of enhanced intracellular ROS levels in an in vivo model of metastatic bladder cancer and the effectiveness of antioxidant adjuvant therapy in this model. Importantly, these studies will establish a novel role for ROS as second messengers in regulating the spatial activation of pro-migratory signaling pathways, further our understanding of the role of mitochondrial ROS in metastatic progression; and determine the therapeutic potential of antioxidants, targeted to inhibit pro-migratory signaling, in metastatic bladder cancer.

癌细胞从原发肿瘤向远处转移的转移是最常见的转移方式。 癌症发展的致命阶段。细胞迁移和侵入的可能性取决于 众多的信号通路，为抗癌治疗提供了新的靶点。反应性 氧物质（ROS）是已知的致瘤性调节剂，并且作为新的第二致瘤因子而发挥作用。 众多细胞信号级联中的信使。ROS的内在水平升高， 多种转移性癌症类型。肿瘤细胞的生存能力和茁壮成长， 增加的活性氧环境表明，它们已经进化到利用亚致死活性氧水平的变化 来驱动促转移信号事件。我们的初步数据表明，皮摩尔亚致死 线粒体衍生的ROS/过氧化氢（H2 O2）的增加导致更高的致瘤性， 在转移性癌细胞中的迁移和侵袭表型，在体外和体内。这些变化 在ROS中导致促迁移信号级联的改变， 关键磷酸酶的失活。此外，这些研究提出了一个新的概念，即H2 O2是一种 调节因子，基本上具有相反的影响，膜定位的亲和抗- 迁移性信号参与者因此，我们假设亚致死性的线粒体增加， ROS的产生调节促迁移信号通路的空间激活， 癌细胞的转移潜能使用转移性膀胱癌模型， 通过以下方式进行测试：1）研究线粒体ROS的细胞作用位点及其在细胞凋亡中的作用。 调节蛋白酪氨酸磷酸酶（PTPs）的氧化和空间分布， 迁移信号2)确定线粒体ROS对局灶性细胞凋亡介质的影响 迁移过程中的粘附激酶信号传导;和3）评估增强的粘附激酶信号传导的后果。 转移性膀胱癌体内模型中的细胞内ROS水平和 抗氧化剂辅助治疗。重要的是，这些研究将建立一个新的作用， ROS作为第二信使调节促迁移信号的空间激活 通路，进一步了解线粒体ROS在转移进展中的作用; 并确定抗氧化剂的治疗潜力，有针对性地抑制促迁移 在转移性膀胱癌中。