Scientists solve 100-year-old cancer mystery

The year 2021 is the 100th anniversary of a fundamental discovery taught in every textbook on biochemistry. In 1921, the German physician Otto Warburg noted that cancer cells harvest energy from glucose sugar in a strangely inefficient way: rather than “burning” it with oxygen, cancer cells do what yeasts do – it ferments it. This oxygen-independent process takes place quickly, but leaves much of the energy in glucose untapped.

Several hypotheses to explain the Warburg effect have been proposed over the years, including the idea that cancer cells are defective mitochondria – their “energy factories” – and therefore unable to perform the controlled metabolism of glucose. But none of these statements stood the test of time. (Cancer cells’ mitochondria, for example, work just fine.)

Now a research team at the Sloan Kettering Institute led by immunologist Ming Li is offering a new answer, based on a solid set of genetic and biochemical experiments and published in the journal on January 21st. Science.

This amounts to an unprecedented link between Warburg metabolism and the activity of a power enzyme in the cell called PI3 kinase.

“PI3 kinase is an important signaling molecule that functions almost like a commander-in-chief of cell metabolism,” says Dr. Li. “Most of the energy cost cellular events in cells, including cell division, occur only when PI3 kinase gives the indication.”

As cells switch to Warburg metabolism, the activity of PI3 kinase is increased, and in turn, the cells’ commitment to division is strengthened. It’s a bit like giving the commander a megaphone.

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

Challenge of the textbook view

Dr. Li and his team, including graduate student Ke Xu, studied the metabolism of Warburg in immune cells, which also rely on this seemingly inefficient form of metabolism. When immune cells are alerted to the presence of an infection, a certain type called T cells shifts from the typical oxygen-burning form of metabolism to Warburg metabolism as they increase in number of growth and infection-fighting machinery.

The key switch that controls this shift is an enzyme called lactate dehydrogenase A (LDHA), which is made in response to PI3 kinase signal. As a result of this switch, glucose remains only partially degraded and the energy coin of the cell, called ATP, is rapidly generated in the cell’s cytosol. (In contrast, when cells use oxygen to burn glucose, the partially degraded molecules move to the mitochondria and are further degraded there to cause ATP with delay.)

Dr. Li and his team found that T cells that do not have LDHA in mice could not maintain their PI3 kinase activity and consequently could not fight infections. For Dr. Li and his team implied that this metabolic enzyme controls the signal activity of a cell.

“The field worked under the assumption that metabolism is secondary to growth factor signaling,” says Dr. Li. “In other words, growth factor signaling drives metabolism, and metabolism supports cell growth and proliferation. The observation that a metabolic enzyme such as LDHA can affect the growth factor signal through PI3 kinase has really caught our attention.”

Like other kinases, PI3 relies on ATP kinase to do its job. Since ATP is the net product of Warburg metabolism, a positive feedback loop is established between Warburg metabolism and PI3 kinase activity, which ensures the continued activity of PI3 kinase – and thus cell division.

Why activated immune cells prefer to use this form of metabolism, Dr Li suspects it has to do with the cells’ need to rapidly produce ATP to promote their cell division and machinery against infection. The positive feedback loop ensures that it is sustained until the infection is eradicated once this program is used.

The cancer compound

Although the team has discovered in immune cells, there are clear parallels with cancer.

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

As with immune cells, cancer cells can use the metabolism of Warburg as a way to maintain the activity of this signaling pathway and thus ensure their continued growth and distribution. The results raise the interesting possibility that doctors could stop cancer growth by blocking the activity of LDHA – the Warburg “switch”.