Researchers have found the chemical pathways that allow some cancers to use fat, instead of sugar, for fuel. The findings will help scientists begin to understand why these types of cancers prefer fat. The study may also lead to the development of new treatments for certain cancers. The details are in a paper that was just published in the journal Molecular Cell.
Most tumor cells use glucose and other sugars as fuel. Oddly, some types of cancer instead prefer to burn fat. Two examples of fat-burning cancers are acute myeloid leukemia and prostate cancer. Cells normally switch to fat when sugar supplies run low but these forms of cancer always prefer fat, even when glucose is available.
A research team from Harvard Medical School investigated the chemical pathways responsible for cells developing a preference for fats. The team focused on a protein called prolyl hydroxylase 3 (PHD3). When cells begin to run out of sugar, a protein called AMPK activates an enzyme called ACC. ACC aids in fat oxidation, helping cells utilize fat as fuel. Once the cell has access to sugar again, though, the cell needs a way to switch back to using sugars. The team found that PHD3 is responsible for this switch. PHD3 activates ACC2, a different version of the ACC enzyme. ACC2 suppresses fat-burning activities, allowing the cell to switch back to metabolizing sugars for fuel. The team predicted that tumor cells with a preference for fat would have low levels of PHD3, allowing them to burn fats even in the presence of sugar.
The research team discovered two cancers with abnormally low levels of PHD3 protein, prostate cancer and acute myeloid leukemia. Both types of cancer prefer fats as a fuel source. The team then brought PHD3 levels up to normal values in cancer cells and in mice with fat-burning tumors. The tumors stopped growing immediately, eventually dying.
The findings provide insights into the role of PHD3 in fat metabolism. Tumor cells that prefer fats to sugar had low levels of PHD3, allowing the cells to bypass mechanisms that normally limit fat-burning. The research team believes that their findings will lead to effective treatments for cancers that use fats as fuel.
Natalie J. German et al. PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2. Molecular Cell (2016).