Researchers at The University of Texas MD Anderson Cancer recently demonstrated that, when compared to normal liver cells, liver tumor cells have a markedly reduced fructose metabolism, and that the KHK (ketohexokinase or fructokinase) gene is differently expressed in tumors, assuming an activity that promotes tumor growth.
These key findings suggest monitoring fructose metabolism as a diagnostic tool for liver cancer, and the altered KHK gene as a potential therapeutic target to treat liver tumors.
The research article, “A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation,” was published in the journal Nature Cell Biology.
Among other essential activities, the liver is the primary site of metabolic breakdown of dietary sugars, namely glucose and fructose, for the production of energy, amino acids, and lipids. In the study, led by Dr. Zhimin Lu, M.D., professor of neuro-oncology, researchers discovered that hepatocarcinoma cells greatly reduce the rate of fructose metabolism and the level of reactive oxygen species.
“We found that liver tumors stopped using fructose. Thus, monitoring fructose metabolism could potentially be used for liver cancer diagnosis,” Lu said in an MD Anderson news release. These findings are important, especially in liver cancer, as symptoms of the malignancy tend to appear only in later stages of the disease, making early diagnoses rare.
The team observed that liver tumor cells expressed the KHK gene. This gene has two enzymatic activities, sugar kinase and protein kinase. Kinases are enzymes that allow cells to transfer phosphate molecules, which in turn play an essential role in energy production and protein regulation mechanisms.
In tumor cells, researchers found a switch from expression of the high-activity fructokinase (KHK)-C to the low-activity KHK-A isoform, which also acts as a protein kinase and enhances tumor cell DNA and RNA synthesis.
Researchers found that KHK-A not only led to the cells’ loss of ability to catalyze fructose, but also promoted liver tumor formation.
“It is this protein kinase activity that we believe can be targeted to treat the liver tumor,” Lu said. “Our study revealed a pivotal mechanism underlying how liver and liver tumor cells use fructose and highlight the instrumental role of the KHK-A protein in promoting tumor development.”