ATP production rate limits cancer growth
Denis Titov, Assistant Adjunct Professor
Nutritional Sciences and Toxicology
Closed. This professor is continuing with Spring 2024 apprentices on this project; no new apprentices needed for Fall 2024.
A distinct metabolic phenotype in cancers is the alteration of glucose metabolism. In general, most cells in the body derive their ATP from respiration. However, most cancer cells generate a substantial fraction of their ATP through glycolysis thereby converting their glucose to lactate and exhibit lower respiration activity. The ability of cancer to covert large amount of glucose to lactate through glycolysis was first noted by Otto Warburg in the 1920s and the phenotype has been deemed the Warburg Effect. It has since been described in organism across all the kingdoms of life, including E. coli, S. cerevisiae, and mammalian cells. Since its discovery, the reason for why the Warburg Effect occurs in cancer cells had remained elusive.
In a recent preprint from our lab, we propose that the Warburg Effect is the result of the optimization of energy metabolism, specifically with respect to producing ATP at a maximal rate for a given glucose availability. We demonstrated that, even though the yield per molecule of glucose is greater for respiration, the maximal ATP production rate is greater for glycolysis than respiration. Therefore, cells shift their energy production strategies towards glycolysis when glucose is nonlimiting to maximize the ATP production rate. We plan to experimentally test our hypothesis that the Warburg Effect arises to produce ATP at the fastest rate given the glucose uptake rate. The immediate aims of the project are to test the following two aims: (1) The ATP production rate is limiting for cell proliferation. (2) Cells grow faster using glycolytic ATP production than respiration.
Role: Over the course of this project, students will gain proficiency with the development of molecular tools used to examine cellular metabolism and aspire to become an independent researcher. Specific techniques will include: (1) tissue culture techniques (2) analyzing Seahorse (quantifies glycolytic vs. respiratory capacity in live cells) (3) mass spectrometry (quantifies metabolite concentrations) data. Students will also gain greater exposure to reading primary research papers and facilitating scientific presentations. Students may learn how to analyze their data in python.
If interest and productivity persist throughout the semester, there will be opportunities to continue this project in future semesters. With greater project involvement, independent research can as the foundation for an honors thesis. All contributions to the advancement of the project will lead to inclusion as an author on future presentations and publications.
Qualifications: Qualifications: Undergraduates seeking to apply should be: (1) highly motivated, organized and engaged, (2) clear communicators (esp. with scheduling & experimental issues), (3) perseverant, and (4) eager to ask questions and learn from mistakes. This position is recommended for those interested in molecular biology and biochemistry, especially as it pertains to cellular metabolism. Previous research experience (although valuable) is not required, but an enthusiasm to learn is essential. Ideally, the apprentice will have some previous, conceptual exposure to molecular biology and cellular metabolism. Highly interested in accepting students of current Sophomore or Junior standing due to the possibility of continuing research in the future, but a current Senior with sufficient previous experience can also be considered.
Day-to-day supervisor for this project: Matt Kukurugya, PhD candidate
Hours: 12 or more hours
Related website: https://denistitovlab.org/
Biological & Health Sciences