How cell growth and proliferation are coordinated with metabolism and the metabolic state of a cell is an important unresolved question that is critical to understanding the metabolic alterations that contribute to cancer. Cancer cells frequently exhibit a highly glycolytic metabolism and consume substantial quantities of glucose to promote proliferation. However, the mechanisms by which glucose and carbon source availability are sensed by a cell as a measure of proliferative capacity remain controversial and poorly understood. Despite renewed interest in cancer metabolism, it has been unclear which aspect of cellular metabolism might represent a realistic, targetable vulnerability of tumors but not normal cells. We recently discovered that acetyl-CoA represents the key metabolite of carbon sources that functions as a critical metabolic signal for growth. Upon entry into growth, cells upregulate the production of acetyl- CoA which consequently induces the acetylation of histones specifically at those genes important for growth. As such, acetyl-CoA enables the expression of these growth genes and thus commitment to proliferation. Preliminary data suggest that a similar metabolic growth control mechanism exists in mammalian cells. These and other considerations have led to the realization that particular enzymes and proteins may play critical roles in fueling the acetyl-CoA- induced growth response pathway. The goal of this proposal is to comprehensively investigate the feasibility of targeting aspects of acetyl-CoA metabolism for the discovery of anti-cancer therapeutics.

Public Health Relevance

We will test the feasibility of targeting a particular non-essential metabolic enzyme for the treatment of certain cancers. We hope these studies will provide novel insights into the mechanisms of cell growth control and contribute towards our understanding of metabolic strategies utilized by cancer cells to support proliferation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA185169-01
Application #
8674809
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Kondapaka, Sudhir B
Project Start
2014-04-01
Project End
2019-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$475,351
Indirect Cost
$176,388
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Comerford, Sarah A; Huang, Zhiguang; Du, Xinlin et al. (2014) Acetate dependence of tumors. Cell 159:1591-602