New research has revealed a potential treatment strategy for acute myeloid leukemia (AML) and other malignancies that show a preference for metabolizing fat over sugar.
The study suggests the protein prolyl hydroxylase 3 (PHD3) is a key regulator of fatty acid oxidation, and PHD3 expression is low in certain malignancies—particularly AML—but overexpressing PHD3 can have anticancer effects.
Researchers believe this finding might aid the development of therapies that work by starving tumors of their fuel.
“This really represents a new frontier in looking at the metabolism of cancer,” said study author Marcia Haigis, PhD, of Harvard Medical School in Boston, Massachusetts.
“Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy.”
Dr Haigis and her colleagues described the work in Molecular Cell.
The researchers knew that when cells run low on nutrients, they switch from sugar to fat as their fuel source to sustain function.
When cells have low energy, the protein AMPK targets the enzyme ACC to activate fat oxidation, which helps cells burn fats to make energy. However, when cells have enough resources, they seek to maintain energy balance.
Dr Haigis and her colleagues were searching for precisely how cells turn off fat oxidation and homed in on PHD3. Recent studies had suggested that PHD3 plays a part in cell metabolism, but,
until now, its precise role has remained unclear.
In a series of experiments, Dr Haigis’s team showed that PHD3 suppressed fat-burning by chemically modifying and activating ACC2—a version of the same enzyme responsible for keeping cellular fat-burning in check.
To determine PHD3’s role in cancer, the researchers combed through databases of all human cancers. The team theorized that sugar-craving malignancies would have high levels of PDH3, and cancers that relied on fat for their energy would have low levels.
The researchers found the lowest levels of PHD3 in AML, so they decided to examine the effects of restoring PHD3 in AML cells and a mouse model of the disease.
The experiments showed that restoring PHD3 expression reduces AML potency, and ACC2 is required for the inhibitory effects of PHD3. Overexpressing PHD3 limited fatty acid oxidation via regulation of ACC2, which decreased leukemia cell proliferation and enhanced survival in the mouse model of AML.
Dr Haigis noted that more basic research is needed before this work can move ahead to the clinic, as it’s still unclear why certain cancers depend on fat.
“What do fats provide to tumors that other fuels don’t?” Dr Haigis asked. “That’s one open question, and this is only the first chapter in the story.”
