Li's team revealed that ATF4-dependent fructose metabolism promotes the malignant progression of gliomas

Glioblastoma multiforme (GBM) is a highly malignant brain tumor
.
Under normal physiological conditions, GBM uses glucose as the main source of energy to support the rapid proliferation of tumor cells, in addition, other nutrients, such as sugars, amino acids and fatty acids, can also be used as GBM energy sources
.
Epidemiological studies have shown that excessive fructose intake is closely related to
tumor malignant progression.
In mammalian cells, the fructose metabolic pathway is different from the initial stage of the glucose metabolic pathway, GLUT5 (encoded by the SLC2A5 gene) is responsible for transporting fructose into the cell, where fructose is phosphorylated by ketohexokinase into fructose 1-phosphate, and then aldolase B cleaves a molecule of 1-phosphate fructose into a molecule of glyceraldehyde and a molecule of dihydroxyacetone phosphate.
Both enter the glycolytic metabolic pathway
by phosphorylation and isomerization by triokinase, respectively, to glyceraldehyde 3-phosphate.

In mammals, the Integrate Stress Response (ISR) can be divided into the following four types: endoplasmic reticulum stress, amino acid deficiency stress, viral infection stress and heme deficiency stress, which correspond to the activation of the following four protein kinases: PERK, GCN2, PKR and HRI
.
Previous studies have shown that these four protein kinases can selectively activate the translation of the transcription factor ATF4 by phosphorylating the protein translation initiation factor eIF2α, and then ATF4 activates the expression of its downstream target gene to complete the cellular stress response program
.

On October 16, 2022, Li Xinjian's research team from the Institute of Biophysics, Chinese Academy of Sciences published an online publication entitled "ATF4-dependent fructolysis fuels growth of glioblastoma multiforme" in the journal Nature Communications.
(https://doi.
org/10.
1038/s41467-022-33859-9) research papers
.
The study revealed that GBM activates cellular ISR under glucose deficiency conditions, and through high-throughput sequencing targeting ATF4 chromatin co-immunoprecipitation (ATF4 ChIP-Seq), the researchers found that ATF4 is able to bind to the promoter region of two key proteins (GLUT5 and ALDOB) encoding genes in the fructose metabolic pathway and activate the expression of these two proteins, disrupting SLC2A5 and ALDOB through gene editing The DNA sequence of the promoter region bound to ATF4 effectively inhibits ISR-induced fructose metabolism
.
Further functional studies showed that blocking ISR-induced fructose metabolism at the gene level and small molecule inhibitor level could significantly inhibit the cell proliferation and clonal formation ability
of GBM under fructose (non-glucose) as the energy supply.
Moreover, in the nude mouse transplant tumor model, the researchers found that ISR caused by glucose deficiency is widely present in GBM tissues, and blocking ISR-induced fructose metabolism can effectively delay the progression
of GBM.
The above evidence suggests that fructose is a substitute energy nutrient for GBM in glucose deficiency conditions, so GBM patients should be wary of a high-fructose diet, and designing small molecule drugs to target fructose metabolism is a potential GBM treatment
.

ATF4-mediated fructose metabolism promotes malignant progression
of gliomas.
Under conditions of energy stress (glucose deficiency), the protein kinases GCN2 and PERK selectively activate the translation of the transcription factor ATF4 by phosphorylating protein translation initiation factor eIF2α, ATF4 binds to the promoter region of SLC2A5 and ALDOB, two key genes in the fructose metabolic pathway, and activates the expression-induced fructose metabolism of these two genes, Provides an energy source for glucose-deficient GBM cells and maintains tumor malignant progression
.

Chen Chao and Zhang Zhenxing, postdoctoral fellows at the Institute of Biophysics, Chinese Academy of Sciences, are the co-first authors of the paper, and researcher Li Xinjian, Institute of Biophysics, Chinese Academy of Sciences, is the corresponding author
of the paper.
The research was supported
by the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the National Key Research and Development Program.

Article link:

(Contributed by: Zeng Yixin/Li Xinjian Research Group)