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Examining Biosynthesis and NAD+ Demand in the Warburg Effect

检查 Warburg 效应中的生物合成和 NAD 需求

基本信息

批准号：
9760789
负责人：
Annamarie Elizabeth Allen
金额：
$ 3.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760789
关键词：
Affect Anabolism Cancer cell line Carbon Carbon Dioxide Cell Culture System Cell Culture Techniques Cell Line Cell Proliferation Cells Characteristics Clinical Consumption Cultured Cells Enzymes Equilibrium Exhibits Generations Genetic Engineering Glucose Glycolysis Growth Kinetics Knowledge Malignant Neoplasms Mathematics Measurement Measures Metabolic Metabolism Methods Mitochondria Modeling Natural regeneration Normal Cell Nucleotide Biosynthesis Nucleotides Nutritional Requirements Outcome Oxides Oxygen Pathogenesis Pathway interactions Pharmaceutical Preparations Prevention therapy Process Production Proliferating Research Role Route Soft tissue sarcoma Source Testing Warburg Effect Work base cancer cell cancer prevention cancer therapy cell growth feeding glucose uptake liquid chromatography mass spectrometry mathematical model metabolomics mouse model neoplastic cell novel therapeutics predictive modeling programs stable isotope targeted cancer therapy

项目摘要

Abstract Cancer cells frequently reprogram metabolism to support increased proliferation, and cancer therapies that target these metabolic demands have been used frequently clinically and show continued promise as new therapeutics. The increased uptake of glucose and its extensive conversion to lactate is the most notable metabolic alteration of cancer cells, and this phenomenon has been termed the ‘Warburg Effect’. During Warburg Effect, significant amounts of glucose are seemingly wasted due to its conversion to lactate, as much of the lactate is excreted from the cell instead of the carbon being used as a biosynthetic building block to produce the molecules required for cell growth and proliferation. However, it is unknown whether the Warburg Effect actually limits cellular biosynthetic capacity, and it is commonly proposed that the Warburg Effect functions to promote a net increase in biosynthesis and thus proliferation. Our lab has recently developed a mathematical model of Warburg Effect, which indicates that Warburg Effect arises to help meet NAD+ demand. The model predicts that Warburg Effect promotes a relatively small increase in biosynthesis by relieving limited NAD+ levels, but further increases in biosynthesis and proliferation entail decreased Warburg Effect. In this proposal, I aim to test the predictions of this model and to thoroughly interrogate the relationship between the Warburg Effect, NAD+ demand, and glucose usage in biosynthesis. To do this, I will first manipulate NAD+ levels using two independent methods in a panel of primary and established cancer cell lines and quantitatively determine whether each cell line decreases its use of the Warburg Effect (Aim I). I will then measure glucose flux into multiple biosynthetic pathways in this panel of cancer cell lines at baseline and during NAD+ modulation, and determine whether the flux of glucose into nucleotide biosynthesis and proliferation is related to the extent of Warburg Effect displayed by each cell line (Aim II). I will extend Aim II by examining whether KA, a drug that selectively disrupts the Warburg Effect, disrupts glucose flux into nucleotide biosynthetic intermediates in a genetically engineered soft- tissue sarcoma mouse model. In cell culture I will determine whether increasing NAD+ levels can rescue this metabolic disruption, as would be predicted by our lab’s model. The proposed work builds upon recent advances our lab has made in understanding the Warburg Effect and will further the collective understanding of how this metabolic phenomenon arises and impacts biosynthesis, a process absolutely necessary for the sustained proliferation of cancer cells. Furthermore, it will determine whether the Warburg Effect imposes biosynthetic vulnerabilities upon cancer cells and help define contexts in which targeting the Warburg Effect will be useful as a cancer therapy.

摘要