Glioblastoma multiforme (GBM) is a highly malignant brain tumor. Under normal physiological conditions, GBM uses glucose as the main energy source to support the rapid proliferation of tumor cells. In addition, other nutrients such as sugar, amino acids and fatty acids can also be used as energy sources for GBM. Epidemiological studies show that excessive intake of fructose is closely related to malignant progression of tumor. In mammalian cells, the fructose metabolic pathway is different from the glucose metabolic pathway at the initial stage. GLUT5 (encoded by SLC2A5 gene) is responsible for transporting fructose into cells, where fructose is phosphorylated by ketohexokinase and converted into fructose-1- phosphate, and then aldolase B splits one molecule of fructose-1- phosphate into one molecule of glyceraldehyde and one molecule of dihydroxyacetone phosphate, which are converted into glyceraldehyde-3- phosphate by phosphorylation and isomerization respectively.
In mammals, Integrate Stress Response (ISR) can be divided into endoplasmic reticulum stress, amino acid deficiency stress, virus infection stress and heme deficiency stress, which correspondingly activate four protein kinases-Perk, GCN2, PKR and HRI. Previous studies have shown that these four protein kinases can selectively activate the translation of transcription factor ATF4 by phosphorylating protein translation initiation factor eIF2α, and then ATF4 activates the expression of its downstream target gene to complete the cell stress response program.
On October 16th, the research team of Li Xinjian from the Institute of Biophysics, Chinese Academy of Sciences published a research paper entitled ATF4-dependent fruitolysis fuels growth of glioblastoma multiform online in Nature Communications. This study revealed that GBM activated cell ISR under the condition of glucose deficiency. By immunoprecipitation of high-throughput sequencing (ATF4 ChIP-Seq) against ATF4 chromatin, it was found that ATF4 could bind to the promoter region of two key proteins (GLUT5 and ALDOB) in fructose metabolism pathway and activate the expression of these two proteins. At the same time, destroying the DNA sequence of SLC2A5 and ALDOB promoter region combined with ATF4 by gene editing could effectively inhibit fructose metabolism induced by ISR. Furthermore, the functional study found that blocking ISR-induced fructose metabolism from gene level and small molecule inhibitor level can significantly inhibit the cell proliferation and clone formation ability of GBM under the condition that fructose (non-glucose) is the energy-supplying substance. In nude mice transplanted tumor model, it was found that ISR caused by glucose deficiency widely existed in GBM tissues, and blocking fructose metabolism induced by ISR could effectively delay the progress of GBM. The above research suggests that fructose is an alternative energy-supplying nutrient for GBM under glucose deficiency.And GBM patients should be wary of high fructose diet. Therefore, designing small molecular drugs to target fructose metabolism is a potential treatment for GBM.
The research work is supported by the National Natural Science Foundation of China, Chinese Academy of Sciences and national key R&D programs.
Paper link
Fructose metabolism mediated by ATF4 promotes malignant progression of glioma. Under the condition of energy stress (glucose deficiency), protein kinases GCN2 and PERK selectively activate the translation of transcription factor ATF4 by phosphorylating protein translation initiation factor eIF2α, and ATF4 binds to the promoter regions of two key genes SLC2A5 and ALDOB in the fructose metabolism pathway and activates fructose metabolism induced by the expression of these two genes, thus providing energy sources for GBM cells with glucose deficiency and maintaining the malignant progress of tumors.