New research led by immunologist Ming Li from Sloan Kettering Institute unpacks a century-old mystery of cancer: why cancer cells get energy from glucose via an oxygen-independent process called the Warburg effect. The study was published recently in the journal Science and explains one of the most significant metabolic mechanisms used by cancer cells.
As Dr. Li describes, the secret is in the connection between an enzyme called PI3 kinase and Warburg metabolism. In the moments when a cancer cell shifts to Warburg metabolism, PI3 kinase increases its activity and promotes division of the cell.
"PI3 kinase is a key signaling molecule that functions almost like a commander-in-chief of cell metabolism," Dr. Li explains. "Most of the energy-costly cellular events in cells, including cell division, occur only when PI3 kinase gives the cue."
Dr. Li and his team conducted their genetic and biochemical experiments in immune cells (T cells), which, similar to cancer cells, use Warburg metabolism when they are fighting an infection. In T cells, this shift is triggered by an enzyme called lactate dehydrogenase A (LDHA), which is made in response to PI3 kinase signaling.
The team’s experiments reconsider the common understanding among biochemists that metabolism is secondary to cell signaling. "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 lactate dehydrogenase A (LDHA) could impact growth factor signaling through PI3 kinase really caught our attention."
Understanding under what particular circumstances T cells choose Warburg metabolism has parallels for cancer cells. It appears that when these cells need to divide quickly, Warburg metabolism, by way of PI3 kinase, is the way to go.
"PI3 kinase is a very, very critical kinase in the context of cancer," Dr. Li says. "It's what sends the growth signal for cancer cells to divide, and is one of the most overly active signaling pathways in cancer."
Not only do these findings revise our understanding of metabolism and cell signaling, they also suggest that targeting metabolism could be an unexplored path to inhibiting cancer growth.