Starving tumours of fat can be a way to kill cancer cells

Certain tumours develop a taste for fat over sugar, which can lay the ground for developing therapies to kill them by starving tumours of their fuel source, suggests a new Harvard study.
Research done by Harvard Medical School (HMS) shows how a signalling pathway that normally
keeps fat-burning in check goes awry in some cancers, reviving up fat consumption and fuelling tumour growth.
Specifically, the study found that a protein called prolyl hydroxylase 3 (PHD3) appears to be a key regulator of the delicate balance inside cells that dampens fat- burning.
The research shows that PHD3 is abnormally low in certain forms of cancer, including acute myeloid leukemia and prostate cancer, a finding that can help lay the ground for development of therapies that work by starving tumours of their fuel.

"This really represents a new frontier in looking at the metabolism of cancer. Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy," said Marcia Haigis, Associate Professor in the HMS.

Biologists have known for some time 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 an enzyme, ACC, to activate fat oxidation, which helps cells burn fats to make energy.
But when cells have enough resources, they seek to maintain energy balance. Even in the face of stress, cells fight to keep this state known as homeostasis. The scientists were searching for precisely how cells turn off fat oxidation. Looking for possible players involved in this delicate balance, the team homed in on the protein PHD3.

A handful of 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, the HMS 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 team combed through scores of databases of all human cancers.
Sugar-craving tumours would have high levels of this fat-burning blocker, to keep sweet-powered energy flowing, the researchers surmised. On the other hand, tumours that relied on fat for their energy would show low levels of PHD3.

Two forms of cancer -- acute myeloid leukemia and prostate cancer -- had by far the lowest PHD3 levels, the analysis showed.
To test their hypothesis that these particular cancers needed fats to survive and that PHD3 was a key regulator in the fat-burning process fuelling tumour growth, the researchers restored to normal the levels of PHD3 in a line of cancer cells and in mice. The tumours not only stopped growing, they died.
Before this discovery can move ahead to the clinic, Haigis said, more basic research needs to be done, both in animal models and in cancer cells taken from patients, to understand why certain tumours depend on fat.

The findings appears in the journal Molecular Cell.