An essential inefficiency

Cancer cells burn sugar using an inefficient metabolic pathway known as fermentation, which captures much less energy as ATP and which most healthy cells—except rapidly proliferating ones, like activated T cells of the immune system—use mainly when starved of oxygen. A study led by Ludwig MIT’s Matthew Vander Heiden and published in December in Molecular Cell examined why this is the case. Matthew and his colleagues show that fermentation, or aerobic glycolysis, helps cells regenerate large quantities of NAD+, a chemical essential to the synthesis of some large molecules like DNA that all cells need to divide. Inhibiting fermentation and forcing cancer cells to make ATP, the currency of cellular energy, through aerobic respiration slowed their growth. When those cells were then additionally treated with a drug that stimulates NAD+ regeneration, however, their proliferative frenzy was restored. Cancer cells, it appears, need NAD+ more than they do ATP. When ATP abounds, aerobic respiration slows down, and so does mitochondrial NAD+ regeneration. Cancer cells and activated T cells, the researchers demonstrate, maintain high levels of NAD+ by employing the less efficient generator of ATP: fermentation. The findings suggest drugs that force cancer cells into aerobic respiration or inhibit NAD+ production could be useful as cancer therapies.

This article appeared in the April 2021 issue of Ludwig Link. Click here to download a PDF (1.4 MB).


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