It was Otto Warburg, the great German physician and Nobel Prize winner, who found back in 1921 that cancer cells do not use sugar as fuel as we thought they would. Instead of “burning” sugar using oxygen like most cells in our body, cancer cells adopt a device used by yeast cells: fermentation.
This specific fermentation process (known as the Warburg effect) is rapid and preferred by cancer cells to produce ATP (used by cells for energy), even in situations where oxygen is available. is. However, this is not the most effective way to tap into all of the energy stored within sugar molecules and so scientists have for many years explained why cancer cells do this.
Many proposed ideas have come up over the years as Warburg coined the term. One hypothesis was that cancer cells have defective mitochondria (the cell’s powerhouse), the organ within the cells where the sugar “burns” and is very effectively turned into energy. However, the hypothesis has not stood the test of time, as it has been found that mitochondria function within cancer cells, as they should, and therefore could not have caused cancer cells to derive energy from sugar Likes the fermentation route.
Now, Dr. Researchers at the Ming Li-led Sloan Catering Institute have published a possible explanation in the journal Science. Using biochemical and genetic experiments, researchers showed that it all comes down to an important growth factor, that of PI3 kinase, an enzyme that has a wide range of cellular activities such as cellular division, proliferation, growth, and survival. Contains.
Dr. “PI3 is a major signaling molecule that acts almost like a commander-in-chief of cell metabolism,” Li said in a statement. “Most of the energy-expensive cellular events in cells, including cell division, occur only when the PI3 kinase is cue.”
PI3 kinase has been extensively studied as part of an important signaling pathway involved in proliferation and cancer metabolism. As cancer cells begin to shift and utilize the Warburg effect, PI3 kinase levels within cells increase. This, in turn, becomes more committed to dividing cells, through a cascade of downstream events. This is certainly a hallmark of cancer: rapid division and spread.
“PI3 kinase is a very important kinase in the context of cancer,” Dr. Lee says. “It sends growth signals to dividing cancer cells, and is one of the most active signaling pathways in cancer.”
To study this, researchers turned to another cell type in our body that has the ability to use the “ineffective” Warburg effect to investigate this phenomenon: immune cells. When certain types of T-cells are informed of nearby infection and need to divide rapidly to increase the number, they are able to turn off the sugar “burning” method of energy production , And turn on the Warburg effect to produce ATP and aid their spread.
As the authors point out in the press release, this “switch” starting from using oxygen to the fermentation process is regulated by an enzyme called lactate dehydrogenase A (LDHA). In turn, LDHA is regulated by the amount of PI3 kinase activity within the cell. Using mice that lack LDHA enzymes, the researchers found that animals could not maintain their normal levels of PI3 kinase within their T-cells, and were unable to fight infection, as T-cells showed PI3K. As the kinase level did not divide properly it should not have.
This reinforces the idea that the metabolic LDHA enzyme was somehow controlling the PI3 kinase signaling molecule of cells.
Dr. “The field operates under the assumption that metabolic growth factor is secondary to signaling,” says Lee. “In other words, growth factor signaling drives metabolism, and metabolism supports cell growth and proliferation.” Therefore the observation that a metabolic enzyme like LDHA can affect growth factor via PI3 kinase actually attracted our attention. “
Researchers point out that like most enzymes, PI3 kinase uses ATP as an active source of energy to perform its functions to implement cellular division. As the Warburg effect eventually culminates in ATP production, a positive feedback loop is established between the two molecules where ATP conducts PI3 kinase activity, and as more PI3 is available, it causes faster cell division. And result in development.
The findings have challenged the accepted textbook view that cell signaling drives metabolism in cancer, as researchers have demonstrated in immune cells that use the Warburg effect, that metabolic enzymes can play signaling molecules that Speeds up cellular division and growth, explaining a long-standing mystery. As to why cancer cells can use the fermentation process preferably to their advantage.
Although more research needs to be done to use cancer cells instead of immune cells to test this, the current findings open an exciting therapeutic avenue in the future where cancer growth by targeting LDHA and May be able to target proliferation, instead commonly focused on PI3 kinase signaling enzymes.