Liver Cancer May Be Diagnosed from Altered Sugar Metabolism

Altered gene expression that causes cancerous cells to metabolize fructose differently from healthy cells could be a significant new biomarker for diagnosing liver cancer.

Dietary fructose is primarily metabolized in the liver and it has now been demonstrated that, compared with normal hepatocytes, hepatocellular carcinoma (HCC) cells markedly reduce the rate of fructose metabolism and the level of reactive oxygen species.

Scientists at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and their colleagues discovered that reduced fructose metabolism in liver tumor cells is caused by aberrant alternative splicing of the Ketohexokinase (Fructokinase, KHK) gene. This resulted in expression of a variety of the gene product called KHK-A, which lost the ability to process fructose. The team showed that KHK-A’s protein kinase activity enhanced tumor cell DNA and ribonucleic acid (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.

The team found that, KHK-A acts as a protein kinase, phosphorylating and activating phosphoribosyl pyrophosphate synthetase 1 (PRPS1) to promote pentose phosphate pathway-dependent de novo nucleic acid synthesis and HCC formation. Furthermore, the V-Myc Avian Myelocytomatosis Viral Oncogene Homolog (c-Myc), Heterogeneous Nuclear Ribonucleoprotein H1/2 (hnRNPH1/2) and KHK-A expression levels and PRPS1 Thr225 phosphorylation levels correlate with each other in HCC specimens and are associated with poor prognosis for HCC.

The authors concluded that their findings reveal a pivotal mechanism underlying the distinct fructose metabolism between HCC cells and normal hepatocytes and highlight the instrumental role of KHK-A protein kinase activity in promoting de novo nucleic acid synthesis and HCC development. Zhimin Lu, MD, PhD, a professor of neuro-oncology and senior author of the study said, “It is this protein kinase activity that we believe can be targeted to treat the liver tumor. 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.” The study was published on April 18, 2016, in the journal Nature Cell Biology.

Related Links:
University of Texas MD Anderson Cancer Center