L-ARGININE AVAILABILITY REGULATES PROLIFERATION OF MALIGNANT T-CELLS

L-精氨酸的可用性调节恶性 T 细胞的增殖

• 批准号: 8360449
• 负责人: Paulo Cesar Rodriguez
• 金额: $ 19.28万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360449
• 关键词: 3' Untranslated Regions; Adult; Amino Acids Activation; Arginine; Binding; Cell Cycle; Cells; Complement; Development; Disease; Funding; G1 Phase; Grant; Half-Life; In Vitro; Inflammatory; Injection of therapeutic agent; Lead; Louisiana; Malignant - descriptor; Malignant Neoplasms; Mediating; Mentors; Messenger RNA; Modeling; Molecular; Mus; National Center for Research Resources; Pathway interactions; Patients; Phosphotransferases; Principal Investigator; Process; Production; RNA-Binding Proteins; Research; Research Infrastructure; Research Personnel; Resources; Solid Neoplasm; Source; Starvation; T-Cell Leukemia; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Translations; United States National Institutes of Health; arginase; cost; cyclin D3; mRNA Stability; novel; outcome forecast; protein expression; response; sensor; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. T cell malignancies have a poor prognosis, especially in adult patients. Therefore new therapies that result in increased response and survival of the patients are urgently needed. We previously demonstrated that Arginase 1 produced by inflammatory cells in solid tumors, arrests the proliferation of normal T cells by depleting L-Arginine and blocking specific pathways. Interestingly, Arginase 1 production is not found in patients with T cell leukemias. We therefore tested whether Arginase 1 would also inhibit T cell leukemia proliferation. Our preliminary results show that malignant T cells require high concentrations L-Arginine (L-Arg) to sustain their high rate of proliferation. In vitro depletion of L-Arg by Arginase I blocks malignant T cell proliferation, and arrests malignant T cells in the G0-G1 phase of the cell cycle by impairing the expression of cyclin D3. We also identified some of the molecular mechanisms involved in this process. The decrease in cyclin D3 protein expression was caused by post-transcriptional mechanisms including a decreased cyclin D3 mRNA stability and an arrest in cyclin D3 translation. The loss of cyclin D3 mRNA half-life induced by the absence of L-Arg was mediated by sequences within the 3'-untranslated region (3'-UTR) of the cyclin D3 mRNA and associated with a low in vitro binding of the RNA-binding protein HuR. Furthermore, the decreased translation of cyclin D3 in the absence of L-Arg correlated with the activation of the amino acid starvation sensor GCN2 kinase. These results support the hypothesis that L-Arg starvation by arginase I blocks malignant T cell proliferation by blocking specific pathways including the expression of cyclin D3. Arginase I can therefore be used in the treatment of T cell lympho-proliferative disorders such as T-ALL. In this study, we propose to identify the molecular mechanisms by which L-Arg depletion impairs malignant T cell proliferation and determine if L-Arg depletion by the injection of Arginase I, or targeting pathways triggered by L-Arg starvation, can be used as a new treatment in T cell leukemias. The initial murine model results demonstrate that the injection of pegylated arginase I (peg-Arg I) prolongs survival in mice bearing T-ALL tumors. Information garnered from this effort may lead to the development of a novel and important therapeutic approach to complement existing therapies for T cell lympho-proliferative disorders such as T-ALL.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 T细胞恶性肿瘤预后不良，尤其是在成人患者中。 因此，迫切需要导致患者反应和存活增加的新疗法。 我们先前证明，实体瘤中的炎性细胞产生的精氨酸酶1通过耗尽L-精氨酸和阻断特定途径来阻止正常T细胞的增殖。有趣的是，在T细胞白血病患者中没有发现精氨酸酶1的产生。 因此，我们测试精氨酸酶1是否也会抑制T细胞白血病增殖。我们的初步结果表明，恶性T细胞需要高浓度的L-精氨酸（L-Arg）来维持其高增殖率。精氨酸酶I在体外消耗L-Arg可阻断恶性T细胞增殖，并通过损害细胞周期蛋白D3的表达将恶性T细胞阻滞在细胞周期的G 0-G1期。 我们还确定了参与这一过程的一些分子机制。细胞周期蛋白D3蛋白表达的减少是由转录后机制引起的，包括细胞周期蛋白D3 mRNA稳定性降低和细胞周期蛋白D3翻译停滞。细胞周期蛋白D3 mRNA的3 '-非翻译区（3'-UTR）内的序列介导的L-Arg的缺乏诱导的细胞周期蛋白D3 mRNA半衰期的损失，并与RNA结合蛋白HuR的体外结合低。此外，细胞周期蛋白D3在L-Arg的情况下翻译的减少与氨基酸饥饿传感器GCN 2激酶的激活相关。 这些结果支持了这样的假设，即L-Arg饥饿通过阻断包括细胞周期蛋白D3的表达在内的特定途径来阻断恶性T细胞增殖。因此，精氨酸酶I可用于治疗T细胞淋巴增殖性疾病，如T-ALL。在这项研究中，我们建议确定L-Arg耗竭损害恶性T细胞增殖的分子机制，并确定通过注射精氨酸酶I或L-Arg饥饿触发的靶向途径来耗竭L-Arg是否可以用作T细胞白血病的新治疗。最初的小鼠模型结果表明，注射聚乙二醇化精氨酸酶I（peg-Arg I）可降低携带T-ALL肿瘤的小鼠的存活率。从这项工作中获得的信息可能会导致开发一种新的和重要的治疗方法，以补充现有的T细胞淋巴增殖性疾病，如T-ALL的治疗。