A study led by The University of Texas MD Anderson Cancer Center found that a gene known as KHK (ketohexokinase or fructokinase) is expressed differently in normal liver tissues versus liver tumors. The findings reveal that liver cancer cells had a much reduced level of fructose metabolism versus healthy cells.
“Normal liver cells catalyze both glucose and fructose for energy, amino acid and lipid production,” said Zhimin Lu, M.D., Ph.D., professor of Neuro-Oncology. “However, we found that liver tumors stopped using fructose. Thus, monitoring fructose metabolism could potentially be used for liver cancer diagnosis.”
Lu’s team discovered that reduced fructose metabolism in liver tumor cells is caused by aberrant alternative splicing of the KHK gene. This resulted in expression of a variety of the gene product called KHK-A, which lost the ability to process fructose.
“KHK-A has two enzymatic activities, sugar kinase and protein kinase,” said Lu. “We discovered that KHK-A was not only a sugar kinase but also a protein kinase.”
The team showed that KHK-A’s protein kinase activity enhanced tumor cell DNA and RNA synthesis and newly identified KHK-A as essential for liver tumor formation. Kinases are enzymes that allow cells to transfer phosphate, crucial for energy production and protein regulation.
“It is this protein kinase activity that we believe can be targeted to treat the liver tumor,” he 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.”
MD Anderson study team participants included Xinjian Li, Ph.D., Xu Qian, Ph.D., Yuhui Jiang, Ph.D., Yanhua Zheng, Ph.D., Yan Xia, Ph.D. and Jong-Ho Lee, Ph.D., all of Neuro-Oncology; David Hawke, Ph.D., Systems Biology; and Gilbert Cote, Ph.D., Endocrine Neoplasia and Hormonal Disorders.
Other participating institutions included Sun Yat-Sen University Cancer Center, Guangzhou, China; Shanghai Jiaotong University, Shanghai; and The University of Texas Graduate School of Biomedical Sciences, Houston.
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