Scientists Solve 100-Year-Old Cancer Mystery

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

Various hypotheses to explain the Warburg effect have been proposed over the years, including the idea that cancer cells have faulty mitochondria – their “energy factories” – and therefore cannot effect controlled combustion of glucose. But none of these explanations have stood the test of time. (Cancer cell mitochondria work very well, for example.)

Now, a research team from the Sloan Kettering Institute led by immunologist Ming Li are proposing a new answer, based on a considerable set of genetic and biochemical experiments and published on January 21 in the journal. Science.

This comes down to a hitherto unrecognized link between Warburg’s metabolism and the activity of a potent enzyme in the cell called PI3 kinase.

“PI3 kinase is a key signaling molecule that functions almost like a commander-in-chief of cell metabolism,” says Dr. Li. “Most of the energy-intensive cellular events in cells, including cell division, occur uniquely when PI3 kinase gives the signal. “

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

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

Challenging the view of the manual

Dr Li and his team, including graduate student Ke Xu, studied Warburg’s metabolism 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 the T-cell changes from the typical form of oxygen-burning metabolism to Warburg’s metabolism as they multiply and speed up the mechanisms. infection control.

The keyswitch 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 is only partially broken down and the cell’s energy currency called ATP is quickly generated in the cell’s cytosol. (In contrast, when cells use oxygen to burn glucose, the partially broken down molecules travel to the mitochondria and are then broken down there to produce ATP with a delay.)

Dr Li and his team found that in mice, T cells lacking LDHA could not maintain their PI3 kinase activity and, therefore, could not effectively fight infections. For Dr. Li and his team, this implied that this metabolic enzyme controlled the signaling activity of a cell.

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

Like other kinases, PI3 kinase relies 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 that PI3 kinase activity continues – and therefore cell division. .

As to why activated immune cells would preferentially use this form of metabolism, Dr. Li suspects it has to do with cells’ need to quickly produce ATP to speed up cell division and their cell-fighting mechanism. infections. The positive feedback loop ensures that once this program is initiated, it will be maintained until the infection is eradicated.

The connection with cancer

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. “This is what sends the signal for the growth of cancer cells to divide, and this is one of the pathways most active cancer signaling. “

As with immune cells, cancer cells can use Warburg’s metabolism as a means of maintaining the activity of this signaling pathway and therefore ensuring their continued growth and division. The findings raise the intriguing possibility that doctors may curb cancer growth by blocking the activity of LDHA – the Warburg “switch”.