The year 2021 marks the 100th anniversary of a basic discovery that is taught in all biochemistry textbooks. In 1921, German physician Otto Warburg discovered that cancer cells extract energy from glucose sugar in a strangely inefficient way: instead of “burning it” using oxygen, cancer cells produce the they do – they ferry it. This oxygen-independent process happens quickly, but leaves much of the energy in glucose unchanged.
A number of theories have been put forward to explain the effects of Warburg over the years, including the notion that cancer cells have deficient mitochondria – their “energy factories” – so they cannot burn under glucose control . But none of these explanations stood the test of time. (Mitochondria of cancer cells work well, for example.)
Now a research team at the Sloan Kettering Institute led by psychologist Ming Li offers a new answer, based on a large set of genetic and biochemical experiments and published January 21 in the journal Science.
It comes down to an unproven link between Warburg metabolism and powerhouse enzyme activity in the cell called PI3 kinase.
PI3 kinase is a major signaling molecule that acts almost as a supercharger on cell metabolism. Most of the cell-energy events in cells, including cell division, occur only when PI3 kinase takes over the cue. “
Dr. Ming Li, Immunologist, Sloan Kettering Institute
As cells move to Warburg metabolism, PI3 kinase activity is increased, which strengthens the cells ’commitment to division. It’s a bit like giving the boss a megaphone.
The findings revise the commonly accepted view among biochemists who view metabolism as a secondary to cell signaling. They also suggest that targeting metabolism may be an effective way to inhibit cancer growth.
Challenging a textbook view
Dr. Li and his team, including graduate student Ke Xu, studied Warburg metabolism in immune cells, which are also responsible for this seemingly inefficient type of metabolism. When immune cells are warned of an infection, a special type called T cells moves from the normal form of oxygen burning to Warburg metabolism as they grow in number and ramp up machinery. fighting infectious.
The main modifier that controls this movement is an enzyme called lactate dehydrogenase A (LDHA), which is produced in response to PI3 kinase signals. As a result of this change, glucose is not yet partially broken down and the cell’s energy charge, called ATP, is rapidly formed in the cytosol of the cell. (In contrast, when cells use oxygen to burn glucose, the partially broken down molecules travel to the mitochondria and are then broken down to make ATP delay.)
Dr. Li and his team found in mice, that T cells with LDHA deficiency could not maintain their PI3 kinase activity, and as a result were unable to fight effectively. Don Dr. Li and his team, this meant that this metabolic enzyme controlled cell signaling activity.
“The field has been working with the hypothesis that secondary metabolism is going to indicate growth factors,” Dr. Li says. “In other words, signaling growth factors directs metabolism, and metabolism supports cell growth and proliferation. Thus the observation that a metabolic enzyme such as LDHA may affect the expression of growth factor via PI3 kinase ar their attention. “
Like other kinases, PI3 kinase relies on ATP to do its job. Because ATP is the net product of Warburg metabolism, a positive feedback loop is established between Warburg metabolism and PI3 kinase activity, confirming continuous PI3 kinase activity – and thus cell division.
As to why activated immune cells prefer this type of metabolism, Dr. Li suspects that it needs to be done with the need for the cells to activate ATP rapidly in order to increase the cell division and infection-fighting machinery. The positive feedback loop ensures that, once this program is in place, it is maintained until the infection is eradicated.
The cancer connection
Although the team did what they found in immune cells, it looks like cancer.
“PI3 kinase is a very important kinase, very important in the context of cancer,” Dr. Li says. “This is what sets the growth signal for cancer cells to divide, and it is one of the most active signaling pathways in cancer.”
Like immune cells, cancer cells can employ Warburg metabolism as a way to maintain the activity of this signaling pathway and thus ensure their continued growth and division. The results raise the interesting possibility that doctors could inhibit cancer growth by inhibiting LDHA activity – the “Warburg” version.
Source:
Sloan Kettering Cancer Memory Center
Magazine Reference:
Xu, K., et al. (2021) Glycolysis fuels the phosphoinositide 3-kinase sign to enhance T cell immunity. Science. doi.org/10.1126/science.abb2683.