Linking Oncogenic Signaling to Tumor Metabolism

将致癌信号传导与肿瘤代谢联系起来

• 批准号: 9477858
• 负责人: Issam BEN-SAHRA
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-17 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9477858
• 关键词: Acute; Adverse effects; Alpha Cell; Amino Acids; Anabolism; Antibodies; Antidiabetic Drugs; Area; Aspartate; Attention; Award; Bioenergetics; Biogenesis; Biological Markers; Bypass; Cancer Model; Carbamoyl Transferases; Carbamyl Phosphate; Cell Line; Cell Proliferation; Cell Survival; Cells; Characteristics; Citric Acid Cycle; Collaborations; Complex; DNA; Data; Dihydroorotase; Doctor of Philosophy; Employee Strikes; Enzymes; Event; Exhibits; FRAP1 gene; Faculty; G6PD gene; Glycolysis; Goals; Growth; Hyperactive behavior; Hypoxanthine Phosphoribosyltransferase; Immunofluorescence Immunologic; Immunohistochemistry; Institution; Ligase; Link; MCF10A cells; Malignant Neoplasms; Measurement; Mentors; Metabolic; Metabolic Control; Metabolic Pathway; Metabolic stress; Metabolism; Metformin; Mitochondria; Modeling; Molecular; Monitor; Normal Cell; Nucleic Acids; Nucleotides; Oncogenes; Oncogenic; Pathway interactions; Patients; Pentosephosphate Pathway; Phase; Phosphorylation; Physiological; Play; Positioning Attribute; Process; Production; Property; Publications; Purines; Pyrimidine; RNA; Regulation; Research; Research Proposals; Research Training; Ribosomal Protein S6 Kinase; Role; Signal Pathway; Signal Transduction; Stimulus; Technology; Testing; Therapeutic; Therapeutic Intervention; Training; Up-Regulation; Work; Xenograft procedure; base; cancer cell; cancer therapy; career; cell growth; chemotherapeutic agent; drug efficacy; graduate student; in vivo; inhibitor/antagonist; interest; killings; knock-down; lipid metabolism; mTOR Inhibitor; macromolecule; metabolomics; neoplastic cell; novel; novel therapeutics; nucleotide metabolism; peer; programs; prostate cancer cell; public health relevance; response; tenure track; therapeutic target; transcription factor; tumor; tumor metabolism; undergraduate student

 DESCRIPTION (provided by applicant): Cancer cells alter their metabolic program to maintain cell autonomous proliferation. Some of the most striking changes of tumor cellular bioenergetics include elevation of glycolysis, increased glutaminolytic flux, up- regulation of amino acid and lipid metabolism, enhancement of mitochondrial biogenesis, induction of the pentose phosphate pathway and macromolecule biosynthesis. My interest in metabolic regulation and cancer led me to undertake my PhD study on the role of metabolic stress inducing agents in prostate cancer cell survival. My PhD work helped to understand the role of metabolic perturbations on cancer cell viability and we were among the first groups in the world to uncover the anti-cancer properties of the anti-diabetic drug metformin. My postdoctoral work revealed a new connection between mTORC1 signaling and metabolic pathways. We showed that mTORC1 activation via a physiological or an oncogenic stimulus, led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway, which serves to make building blocks of RNA and DNA required for anabolic cell growth and proliferation. mTORC1 signaling post-translationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates Ser1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), an enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. My goal is to investigate the molecular links between cellular metabolism and oncogenic events. Ultimately, my long-term career goal is to obtain a tenure-track faculty position at an academic institution where I will be able to expand my area of research, train and instruct graduate and undergraduate students and collaborate with my academic peers. The research proposed in the mentored phase of this application will focus on the role of Ser1859 phosphorylation of CAD in tumor metabolism and the role of mTORC1 on de novo purine synthesis. The research outlined in the independent phase will seek to identify novel connections between oncogenic and physiological signals and the de novo and salvage nucleotide synthesis to uncover a potential therapeutic target to specifically kill tumor cells. Th initial discovery that cancer cells exhibit atypical metabolic characteristics can be traced to the pioneering work of Otto Warburg, over the first half of the twentieth century. Deciphering the interplay between oncogenic processes and metabolic pathways that contribute to metabolic reprogramming in a given setting may serve as the critical factor in determining therapeutic targets that enable maximal drug efficacy with minimal deleterious effect on normal cells. Ultimately, my research proposal will ideally facilitate further progress in capitalizing upon the exploitation of atypical metabolic features in cancer as a means of therapeutic intervention.

 描述（由申请人提供）：癌细胞改变其代谢程序以维持细胞自主增殖。肿瘤细胞生物能学的一些最显着的变化包括糖酵解的升高、谷氨酰胺分解通量的增加、氨基酸和脂质代谢的上调、线粒体生物发生的增强、磷酸戊糖途径的诱导和大分子生物合成。我对代谢调节和癌症的兴趣促使我进行了博士研究，研究代谢应激诱导剂在前列腺癌细胞存活中的作用。我的博士工作有助于了解代谢扰动对癌细胞活力的作用，我们是世界上第一批发现抗糖尿病药物二甲双胍的抗癌特性的团队之一。我的博士后工作揭示了 mTORC1 信号传导与代谢途径之间的新联系。我们发现，mTORC1 通过生理或致癌刺激激活，导致通过从头嘧啶合成途径的代谢流的急性刺激，该途径用于制造合成代谢细胞生长和增殖所需的 RNA 和 DNA 的构建模块。 mTORC1 信号转译后通过其下游靶核糖体蛋白 S6 激酶 1 (S6K1) 调节该代谢途径，该激酶直接磷酸化 CAD（氨甲酰磷酸合成酶 2、天冬氨酸转氨甲酰酶、二氢乳清酶）上的 Ser1859，CAD 是一种催化代谢的前三个步骤的酶。 新嘧啶合成。我的目标是研究细胞代谢和致癌事件之间的分子联系。最终，我的长期职业目标是在学术机构获得终身教职，在那里我将能够扩大我的研究领域，培训和指导研究生和本科生，并与我的学术同行合作。本申请指导阶段提出的研究将重点关注 CAD Ser1859 磷酸化在肿瘤代谢中的作用以及 mTORC1 在嘌呤从头合成中的作用。独立阶段概述的研究将寻求确定致癌和生理信号以及从头和挽救核苷酸合成之间的新联系，以发现特异性杀死肿瘤细胞的潜在治疗靶点。癌细胞表现出非典型代谢特征的最初发现可以追溯到 奥托·瓦尔堡 (Otto Warburg) 在二十世纪上半叶的开创性工作。破译致癌过程和代谢途径之间的相互作用，在特定环境下促进代谢重编程，可能是确定治疗靶点的关键因素，从而实现最大的药物疗效，同时对正常细胞的有害影响最小。最终，我的研究计划将理想地促进利用癌症非典型代谢特征作为治疗干预手段的进一步进展。