MIT biologists might have found the answer to why cancer cells do not metabolize sugar the same way the healthy cells do. In a study that appeared in Molecular Cell, the biologists show that this pathway helps cells to regenerate large quantities of a molecule called NAD+ which they need to synthesize DNA and other important molecules.
Matthew Vander Heiden, an associate professor of biology at MIT and associate director of MIT’s Koch Institute for Integrative Cancer Research, is the senior author of this study, said, “What we found is that under certain circumstances, cells need to do more of these electron transfer reactions, which require NAD+, in order to make molecules such as DNA.”
In this study, the MIT team tried to answer the question pertaining to cancer cells; the ability to perform fermentation, and what the result would be if they suppressed that particular ability. The researchers treated the cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway. It slowed down the cancer cells’ growth.
To work on cells’ ability to regenerate, the researchers tried to stimulate the cells to produce NAD+. They found that the cells started regenerating rapidly although they could not perform fermentation.
The researchers came to the conclusion that during the period when the cells are growing rapidly, they need NAD+ more than ATP. “We hypothesized that when you make both NAD+ and ATP together if you can’t get rid of ATP, it’s going to back up the whole system such that you also cannot make NAD+,” Li says. “If you step back and look at the pathways, what you realize is that fermentation allows you to generate NAD+ in an uncoupled way,” said Luengo.
Testing this idea on other proliferating cells, the researchers found that allowing alternative methods of NAD+ production helps cells to continue rapidly dividing.
They also observed the same phenomenon in nonmammalian cells such as yeast. “Not all proliferating cells have to do this,” Vander Heiden says. “It’s really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they’re burning, that’s when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed.”
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, 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.