THE ROLE OF CLASS III PI-3 KINASE IN MTOR COMPLEX1 SIGNALING AND TUMORIGENESIS

III 类 PI-3 激酶在 MTOR 复合物 1 信号传导和肿瘤发生中的作用

• 批准号: 8200905
• 负责人: Brian Michael Wiczer
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8200905
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Address; Amino Acid Transporter; Amino Acids; Anchorage-Independent Growth; Automobile Driving; Branched-Chain Amino Acids; Cancer Etiology; Carbohydrates; Catalytic Domain; Cause of Death; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Cessation of life; Complex; Confocal Microscopy; Consumption; Diet; Energy Intake; Epidemic; Epidemiologic Studies; Fatty acid glycerol esters; Glioblastoma; Goals; Half-Life; Hela Cells; Human; Immunofluorescence Immunologic; In Situ; Laboratories; Length; Letters; Malignant Neoplasms; Measures; Mediating; Mitogens; Molecular; Morbidity - disease rate; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Parents; Phosphatidylinositols; Phosphotransferases; Proteins; RNA Interference; Research; Research Personnel; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Sirolimus; Small Interfering RNA; Staging; Testing; Tetanus Helper Peptide; Therapeutic Intervention; Training; Variant; Western World; Xenograft Model; base; cancer therapy; cancer type; career; cell growth; effectiveness measure; experience; genetic manipulation; human FRAP1 protein; in vivo Model; mTOR Inhibitor; mTOR inhibition; mTOR protein; metaplastic cell transformation; novel; programs; response; stable cell line; subcutaneous; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Cancer has become the leading cause of morbidity and death worldwide, with annual deaths expected to reach 10.3 million by 2020. Recent epidemiological studies have shown that a dramatic rise in obesity and the associated type 2 diabetes are major risk factors for cancer. These observations have stimulated the critical need to identify the molecular signaling pathways that drive tumorigenesis in response to the obese setting, such that novel therapies can be developed. Although increased fats and carbohydrates are commonly cited as the major factors in diet-induced dysmetabolic states, increased protein consumption has also emerged as a potential contributor, acting through elevated levels of circulating branched-chain amino acids (BCAAs). BCAA transporters are upregulated in many cancer types and their increased expression correlates with the stage of malignancy, suggesting that increased BCAA availability and enhanced BCAA influx may be sufficient to drive tumorigenesis. The mamalian target of rapamycin complex1 (mTORC1) acts as a regulatory node by integrating input from nutrients and mitogens to positively control cell growth and proliferation. Critically, the mechanism by which BCAAs promote malignancy appears to be mechanistically dependent on BCAA-induced mTORC1 signaling. Class III phosphatidylinositol-3OH kinase (PI3K), a heterodimer consisting of the catalytic subunit, hVps34, and a regulatory subunit, hVps15, mediates the response to nutrient input to mTORC1. Class III PI3K is also required for Src- dependent tumorigenesis. The key role of class III PI3K in the mTORC1-dependent nutrient response and tumorigenesis suggests that targeting class III PI3K may prove to be a novel and efficacious anti- cancer therapy. The long-term goal of this proposal is to delineate the mechanisms through which the class III PI3K mediates nutrient-induced mTORC1 signaling and to examine the role of the class III PI3K in promoting tumorigenesis and tumor progression. The central hypothesis is that the tumorigenic role of class III PI3K is manifested through the mTORC1 signaling pathway and that class III PI3K is a candidate for therapeutic intervention. To address this central hypothesis, two specific aims will be pursued. Aim 1 is to test the hypothesis that the class III PI3K regulatory subunit, hVps15, positively regulates mTOR protein stability and cellular localization. Aim 2 is to test the hypothesis that hVps15 is necessary for tumorigenesis. These specific aims will be achieved through genetic manipulation of hVps15 in cell culture, assessment of mTORC1 signaling, and determination of mTOR protein half-life. In situ and in vivo models of tumorigenesis, in conjunction with RNAi-based disruption of hVps15 and pharmacological inhibition of mTOR, will be used to examine the role of the class III PI3K in tumorigenesis. PUBLIC HEALTH RELEVANCE: Deaths caused by cancer are continuing to rise worldwide, and are, in large part, thought to be accompanying the escalating obesity epidemic. Excess nutrients are strong drivers of cancer. Thus, this proposal aims to understand how nutrient-regulated signals promote cancer, and to obtain a deeper understanding of the nutrient-regulated signaling pathways themselves as a first step in developing more effective cancer therapies.

描述(申请人提供)：癌症已成为全球发病率和死亡的主要原因，预计到2020年，每年的死亡人数将达到1030万。最近的流行病学研究表明，肥胖症和相关的2型糖尿病的急剧上升是癌症的主要危险因素。这些观察结果刺激了识别驱动肿瘤发生的分子信号通路以响应肥胖环境的迫切需要，以便开发新的治疗方法。虽然脂肪和碳水化合物的增加通常被认为是饮食诱导的代谢紊乱状态的主要因素，但蛋白质消耗的增加也是一个潜在的因素，其作用机制是循环中支链氨基酸(BCAA)水平的升高。支链氨基酸转运体在许多癌症类型中表达上调，其表达增加与恶性肿瘤的分期相关，提示支链氨基酸可获得性增加和支链氨基酸内流增加可能足以推动肿瘤的发生。哺乳动物靶标雷帕霉素复合体1(MTORC1)通过整合营养物质和有丝分裂原的输入，发挥调控节点的作用，积极控制细胞的生长和增殖。关键的是，支链氨基酸促进恶性肿瘤的机制似乎机械地依赖于支链氨基酸诱导的mTORC1信号。III类磷脂酰肌醇-3OH激酶(PI3K)是一种异源二聚体，由催化亚基hVps34和调节亚基hVps15组成，介导对mTORC1营养输入的反应。III类PI3K也是依赖于Src的肿瘤发生所必需的。III类PI3K在mTORC1依赖的营养反应和肿瘤发生中的关键作用表明，靶向III类PI3K可能被证明是一种新的有效的抗癌治疗方法。这项提议的长期目标是描述III类PI3K介导营养诱导的mTORC1信号的机制，并研究III类PI3K在促进肿瘤发生和肿瘤进展中的作用。核心假设是，III类PI3K的致瘤作用是通过mTORC1信号通路表现出来的，并且III类PI3K是治疗干预的候选者。为了解决这一核心假设，将追求两个具体目标。目的1是验证III类PI3K调节亚基hVps15正向调节mTOR蛋白稳定性和细胞定位的假设。目的2是验证hVps15在肿瘤发生中的必要性这一假说。这些特定的目标将通过在细胞培养中对hVps15进行遗传操作、评估mTORC1信号和测定mTOR蛋白半衰期来实现。肿瘤发生的原位和体内模型，以及基于RNAi的hVps15的破坏和mTOR的药理抑制，将被用于研究III类PI3K在肿瘤发生中的作用。 与公共卫生相关：癌症导致的死亡在全球范围内继续上升，而且在很大程度上被认为是伴随着不断升级的肥胖症流行的。过多的营养物质是癌症的强烈驱动力。因此，这项建议旨在了解营养调节信号如何促进癌症，并更深入地了解营养调节信号通路本身，作为开发更有效的癌症治疗的第一步。