Linking Oncogenic Signaling to Tumor Metabolism

将致癌信号传导与肿瘤代谢联系起来

基本信息

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
项目类别：
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

项目摘要

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自主细胞增殖，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、增强。线粒体生物发生、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关于代谢应激诱导剂在前列腺癌细胞存活中的作用的博士研究。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通量的急剧刺激，该途径用于制造 RNA 和 DNA 所需的构建模块。 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。催化嘧啶从头合成的前三个步骤我的目标是研究。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。本科生并与我的学术同行合作，在本申请的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 在独立阶段概述的研究。将寻求确定致癌信号和生理信号以及从头合成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标。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是破译在特定环境下促进代谢重编程的致癌过程和代谢途径之间的相互作用，这可能是确定治疗目标的关键因素，从而以最小的代价实现最大的药物疗效。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。