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In the 1920s, German chemist Otto Warburg discovered that cancer cells do not metabolize sugar in the same way healthy cells do. Since then, scientists have tried to understand why cancer cells use this alternative route, which is much less effective.
MIT biologists have now found a possible answer to this long-standing question. In a study published in Molecular Cell, they showed that this metabolic pathway, known as fermentation, helps cells regenerate large amounts of a molecule called NAD +, which they need to synthesize DNA and other important molecules. Their findings also explain why other rapidly proliferating cell types, such as immune cells, go through fermentation.
“It really has been a century-old paradox that many people have tried to explain in different ways,” says Matthew Vander Heiden, associate professor of biology at MIT and associate director of the Koch Institute for Integrative Cancer Research at MIT. “What we found is that under certain circumstances cells have to do more of these electron transfer reactions, which require NAD +, in order to make molecules like DNA.
Vander Heiden is the lead author of the new study, and lead authors are former MIT graduate student and post-doctoral fellow Alba Luengo PhD ’18 and graduate student Zhaoqi Li.
Inefficient metabolism
Fermentation is a way for cells to convert the energy in sugar into ATP, a chemical that cells use to store energy for all their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which produces much more ATP. Cells usually only go through fermentation when they do not have enough oxygen to perform aerobic respiration.
Since Warburg’s discovery, scientists have advanced numerous theories as to why cancer cells go through the inefficient fermentation pathway. Warburg initially proposed that the mitochondria of cancer cells, where aerobic respiration occurs, could be damaged, but this did not turn out to be the case. Other explanations have focused on the possible benefits of ATP production in a different way, but none of these theories have gained broad support.
In this study, the MIT team decided to try to find a solution by asking what would happen if they suppressed the ability of cancer cells to perform fermentation. To do this, they treated the cells with a drug that causes them to divert a molecule called pyruvate from the fermentation pathway to the aerobic respiration pathway.
They saw, as others have shown previously, that blocking fermentation slows the growth of cancer cells. Then they tried to figure out how to restore the cells’ ability to proliferate, while blocking fermentation. One approach they tried was to stimulate cells to produce NAD +, a molecule that helps cells get rid of extra electrons that are shed when cells make molecules like DNA and proteins. .
When the researchers treated the cells with a drug that stimulates the production of NAD +, they found that the cells began to proliferate quickly, even though they still couldn’t ferment. This has led researchers to theorize that when cells are growing rapidly, they need NAD + more than ATP. During aerobic respiration, cells produce a lot of ATP and some NAD +. If the cells accumulate more ATP than they can use, respiration slows down and the production of NAD + also slows down.
“We hypothesized that when you create both NAD + and ATP together, if you can’t get rid of ATP, it’s going to back up the whole system so you can’t make it either. NAD +, ”says Li.
Therefore, switching to a less efficient method of producing ATP, which allows cells to generate more NAD +, actually helps them grow faster. “If you take a step back and look at the tracks, what you realize is that fermentation allows you to generate NAD + in a decoupled way,” says Luengo.
Solve the paradox
The researchers tested this idea in other rapidly proliferating cell types, including immune cells, and found that blocking fermentation but using alternative methods of producing NAD + allowed cells to continue to grow. divide quickly. They also observed the same phenomenon in non-mammalian cells such as yeast, which perform a different type of fermentation that produces ethanol.
“Not all proliferating cells have to do this,” says Vander Heiden. “These are really just cells that are growing very quickly. If cells are growing so quickly that their demand for manufacturing exceeds the amount of ATP they burn, that’s when they fall into this type of metabolism. So that resolves, in my mind, many paradoxes that have existed.
The results suggest that drugs that force cancer cells to return to aerobic respiration instead of fermentation may offer a possible way to treat tumors. Drugs that inhibit the production of NAD + may also have a beneficial effect, the researchers say.
The research was funded by the Ludwig Center for Molecular Oncology, the National Science Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the Medical Research Council, the NHS Blood and Transplant, the Novo Nordisk Foundation, the Knut and Alice Wallenberg Foundation, Stand Up 2 Cancer, the Lustgarten Foundation and the MIT Center for Precision Cancer Medicine.
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