Scientists solve a 100-year cancer mystery

The year 2021 marks the 100th anniversary of a fundamental discovery that is taught in all biochemistry books. In 1921, German doctor Otto Warburg observed that cancer cells harvest energy from glucose sugar in a strangely inefficient way: instead of “burning it” using oxygen, cancer cells do what yeast does – they ferment it. This oxygen-independent process occurs quickly, but leaves much of the glucose energy untapped.

Several hypotheses to explain the Warburg effect have been proposed over the years, including the idea that cancer cells have defective mitochondria – their “energy factories” – and therefore cannot carry out controlled glucose burning. But none of these explanations have stood the test of time. (The mitochondria of cancer cells work well, for example.)

Now, a research team at the Sloan Kettering Institute led by immunologist Ming Li offers a new answer, based on a robust set of genetic and biochemical experiments and published on January 21 in the newspaper Science.

It all comes down to a hitherto unappreciated link between Warburg’s metabolism and the activity of a central enzyme in the cell called PI3 kinase.

“PI3 kinase is a key signaling molecule that works almost like a chief commander of cell metabolism,” says Dr. Li. “Most cellular events with high energy costs in cells, including cell division, occur only when PI3 kinase gives the clue. “

As the cells switch to Warburg metabolism, PI3 kinase activity increases and, in turn, the cells’ commitment to divide is strengthened. It’s like giving the commander-in-chief a megaphone.

The findings revise the commonly accepted view among biochemists who view metabolism as secondary to cell signaling. They also suggest that targeting metabolism may be an effective way to stop cancer growth.

Challenging the textbook view

Dr. Li and his team, including graduate student Ke Xu, studied Warburg’s metabolism in immune cells, which also depend on this seemingly inefficient form of metabolism. When cells of the immune system are alerted to the presence of an infection, a certain type of T cell changes from the typical form of oxygen-burning metabolism to Warburg’s metabolism as it grows in number and increases the mechanism for fighting infections.

The key that controls this change is an enzyme called lactate dehydrogenase A (LDHA), which is made in response to PI3 kinase signaling. As a result of this change, glucose remains only partially broken down and the cell’s energy currency, called ATP, is generated quickly in the cell’s cytosol. (In contrast, when cells use oxygen to burn glucose, the partially broken molecules travel to the mitochondria and are later broken down there to produce ATP in a delay.)

Dr. Li and his team found that, in mice, T cells without LDHA could not sustain their PI3 kinase activity and, as a result, could not effectively fight infections. For Dr. Li and his team, this implied that this metabolic enzyme was controlling a cell’s signaling activity.

“The field worked on the assumption that metabolism is secondary to growth factor signaling,” says Dr. Li. “In other words, growth factor signaling boosts metabolism, and the metabolism supports growth and Therefore, the observation that a metabolic enzyme such as LDHA could impact growth factor signaling through PI3 kinase really caught our attention. “

Like other kinases, PI3 kinase depends on ATP to do its job. Since ATP is the net product of Warburg’s metabolism, a positive feedback loop is established between Warburg’s metabolism and PI3 kinase activity, ensuring continuous PI3 kinase activity – and therefore cell division.

As to why the activated immune cells prefer to use this form of metabolism, Dr. Li suspects that this has to do with the cells’ need to produce ATP quickly to increase their cell division and infection-fighting machinery. The positive feedback cycle ensures that, once this program is started, it will be maintained until the infection is eradicated.

The Cancer Connection

Although the team made their discoveries in immune cells, there are clear parallels to cancer.

“PI3 kinase is a very, very critical kinase in the context of cancer,” says Dr. Li. “It is what sends the growth signal to cancer cells to divide and is one of the most active signaling pathways for cancer. “

As with immune cells, cancer cells can employ Warburg metabolism as a way to maintain the activity of this signaling pathway and, therefore, ensure its continuous growth and division. The results raise the intriguing possibility that doctors can stem the growth of cancer by blocking the activity of LDHA – Warburg’s “switch”.