Cancer cells often choose a seemingly inefficient way of producing energy, even when higher-yielding alternatives are available.
Rather than utilizing the body’s available stores of oxygen to break down glucose and generate a large amount of energy via a process known as respiration, cancer cells routinely favor glycolysis—a metabolic pathway that yields a low amount of energy—to meet a large part of their energy needs. This phenomenon, known as the Warburg Effect in honor of the German physiologist who first observed it in the 1920s, has puzzled scientists for nearly a century.
But a new UC Berkeley study published today in the Proceedings of the National Academy of Sciences provides compelling insight: cancer cells prioritize glycolysis because it produces adenosine triphosphate (ATP), the molecule that all living cells use for energy, at a faster rate than cellular respiration.
PhD student Matthew Kukurugya sits in front of a whiteboard with the main mathematical equations central to supporting their hypothesis. Photo courtesy of Kukurugya.
“Until now, there had been no widely accepted explanation as to why the Warburg Effect occurs,” explained Denis Titov, a professor in the Department of Nutritional Sciences and Toxicology and researcher at the Center for Computational Biology, who co-authored the study with Molecular and Cell Biology PhD student Matthew Kukurugya. “People have tried to propose various theories and hypotheses, but our study strongly supports one hypothesis, which we hope will now gain wider acceptance.”
For the study, Kukurugya, Titov, and their collaborator Saharon Rosset of Tel Aviv University developed a “unifying set of equations” that uses key biochemical parameters like ATP yield, rate of ATP production, and the proportion of a cell’s physical space used to produce ATP to predict the Warburg Effect. Their model suggested that cancer cells favor glycolysis because it produces ATP at a faster rate than respiration. They validated their findings via experiments measuring the specific activities of glycolysis and respiration in mammalian cancer cells, a strain of E. coli bacteria, and brewer's yeast (Saccharomyces cerevisiae).
“While respiration is a more efficient way of producing ATP, cancer and other fast-growing cells prioritize glycolysis because of how quick it is,” Kukurugya said. He likened their findings to the considerations people make when planning travel. “If you were planning a trip but wanted to be economical about it, you might travel by bus or train. But if all you cared about was how fast you got there, then you would book a flight—even if the only remaining option is in first class.”
The authors hope the model can offer additional researchers a starting point for investigations into the mechanisms that both cancerous and non-cancerous cells use to optimize their energy metabolism. For instance, Titov said the model might help explain why fast-twitch muscle fibers—which are used for short bursts of intense activity—evolved to use glycolysis to generate energy rather than respiration.
Read the full study on the Proceedings of the Natural Academy of Sciences website.