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Autumn 2016


cancer; cell biology

microscopic view of acute myloid leukemia cells
Acute myeloid leukemia

Cancers are such notorious sugar addicts that PET scans searching for the disease light up when they detect sugar-gobbling tumor cells. But a handful of cancers appear to favor fat over sugar, a fact that has long mystified scientists. Now, an HMS study shows how certain tumors develop a taste for fat as their life-sustaining fuel.

The findings, published September 15 in Molecular Cell, show how a signaling pathway that normally keeps fat-burning in check goes awry in some cancers, revving up fat consumption and fueling tumor growth.

The study found that the protein prolyl hydroxylase 3 (PHD3) appears to be key to regulating cellular mechanisms that dampen fat-burning. That protein, the research shows, is abnormally low in certain forms of cancer, including acute myeloid leukemia and prostate cancer.

Biologists have known for some time that when cells run low on nutrients they switch from burning sugar to burning fat for fuel.  

When cells have low energy, the protein AMPK targets an enzyme, ACC, to activate fat oxidation, which helps cells burn fats to make energy. The team wanted to know how cells turn off fat oxidation.

They homed in on the protein PHD3; a handful of recent studies had suggested it plays a role in cell metabolism.

In a series of experiments, the HMS research team showed that PHD3 suppressed fat-burning by chemically modifying and activating a version of ACC responsible for keeping cellular fat-burning in check. When the scientists restored to normal the levels of PHD3 in a line of cancer cells and in mice, the tumors not only stopped growing, they died.

“This really represents a new frontier in looking at the metabolism of cancer,” says Marcia Haigis, an HMS associate professor of cell biology and senior author of the paper. “This is one of the few pathways we’ve modulated where we really see the tumors die. They are so dependent on fat oxidation that they die.”

Image: Pr. J. Bernard/CNRI/Science Source

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