Mechanism Behind Warburg Effect Explained

Researchers from Sloan Kettering Institute say they have found a mechanistic explanation for the Warburg effect observed in cancer cells. Their research was published yesterday in Science.

It comes down to a previously unappreciated link between Warburg metabolism and the activity of PI3 kinase, according to senior author Ming Li. "Most of the energy-costly cellular events in cells, including cell division, occur only when PI3 kinase gives the cue." As cells shift to Warburg metabolism, the activity of PI3 kinase is increased, and in turn, the cells' commitment to divide is strengthened.

Dr. Li and his team studied Warburg metabolism in immune cells. When immune cells are alerted to the presence of an infection, T cells shift from the typical oxygen-burning form of metabolism to Warburg metabolism as they grow in number and ramp up infection-fighting machinery. The key switch that controls this shift is lactate dehydrogenase A (LDHA), which is made in response to PI3 kinase signaling.

Dr. Li and his team found that in mice, T cells lacking LDHA could not sustain their PI3 kinase activity, and as a result could not effectively fight infections. To Dr. Li and his team, this implied that this metabolic enzyme was controlling a cell's signaling activity.

"The field has worked under the assumption that metabolism is secondary to growth factor signaling," Dr. Li says. "In other words, growth factor signaling drives metabolism, and metabolism supports cell growth and proliferation. So the observation that a metabolic enzyme like LDHA could impact growth factor signaling through PI3 kinase really caught our attention."

Like other kinases, PI3 kinase relies on ATP to do its work. Since ATP is the net product of Warburg metabolism, a positive feedback loop is set up between Warburg metabolism and PI3 kinase activity, securing PI3 kinase's continued activity -- and therefore cell division.