Linking oncogenic signaling to tumor metabolism

将致癌信号与肿瘤代谢联系起来

基本信息

批准号：
8868257
负责人：
Issam BEN-SAHRA
金额：
$ 9.73万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8868257
关键词：
Acute Adverse effects 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 Faculty G6PD gene Glycolysis Goals Growth Guanine Health Hypoxanthines Immunofluorescence Immunologic Immunohistochemistry Institution Ligase Link MCF10A cells Malignant Neoplasms Measurement Mentors Metabolic 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 Sirolimus Stimulus Technology Testing Therapeutic Therapeutic Intervention Training Transferase Up-Regulation Work Xenograft procedure base cancer cell cancer therapy career cell growth chemotherapeutic agent drug efficacy graduate student human FRAP1 protein in vivo inhibitor/antagonist interest killings lipid metabolism mTOR Inhibitor macromolecule metabolomics neoplastic cell novel novel therapeutics nucleotide metabolism peer programs prostate cancer cell purine response 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（由应用提供）：癌细胞改变其代谢程序以维持细胞自主增殖。肿瘤细胞生物能源的一些最引人注目的变化包括糖酵解的升高，增加的谷氨酰胺溶解通量，氨基酸的上调和脂质代谢，线粒体生物发生的增强，五磷酸盐途径诱导的诱导和五磷酸盐途径和杂质分子生物生物合成。我对代谢调节和癌症的兴趣使我对代谢胁迫诱导药物在前列腺癌细胞存活中的作用的作用进行了博士学位研究。我的博士学位工作有助于了解代谢扰动对癌细胞生存能力的作用，我们是世界上首批揭示抗糖尿病药物二甲双胍的抗癌特性的人。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。我们表明，MTORC1通过生理或致癌刺激激活，导致急性刺激通过从头嘧啶的合成途径刺激代谢通量，该途径是使合成代谢细胞生长和增殖所需的RNA和DNA的构件的构建块。 MTORC1在翻译后信号传导通过其下游靶标核糖体蛋白S6激酶1（S6K1）在CAD上直接磷酸化Ser1859（Carbamoyl-磷酸磷酸酯酶2，天冬氨酸型trandcarbamoylase，dihydrorortase and Entihy nevems and Entempase）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一个学术机构中获得终身教师职位，我将能够扩大我的研究，培训和指导研究生和本科生的研究领域，并与我的学术同伴合作。在本应用的修订阶段提出的研究将重点介绍CAD在肿瘤代谢中的Ser1859光谱化的作用以及MTORC1在从头纯合成中的作用。在独立阶段概述的研究将寻求确定致癌和物理信号之间的新连接以及从头和挽救核苷酸合成，以发现潜在的治疗靶标，以特别杀死肿瘤细胞。最初发现的，暴露于非典型代谢特征的癌细胞可以追溯到奥托·沃堡（Otto Warburg）的开创性工作，在20世纪上半叶。在给定环境中有助于代谢重编程的致癌过程和代谢途径之间的相互作用可能是确定治疗靶标的关键因素，从而使最大的药物效率能够对正常细胞产生最小的有害作用。最终，理想情况下，我的研究建议将促进进一步的进步，以剥削癌症的非典型代谢特征作为治疗干预措施。