Glioblastoma multiforme (GBM) is a highly malignant brain tumor. A highly active glucose metabolism would accelerate glucose consumption, resulting in the stress of glucose deprivation in the GBM microenvironment. However, it is unclear how cancer cells adapt to and overcome this environment stress. 

In mammals, Integrate Stress Response (ISR) includes four types, i.e., endoplasmic reticulum stress, amino acid deprivation stress, viral infection stress and heme deprivation stress, corresponding to the activation of four protein kinases, i.e., PERK, GCN2, PKR and HRI. Previous studies have shown that these protein kinases can selectively activate the translation of the transcription factor ATF4 by phosphorylating the protein translation initiation factor eIF2α, thereby activating the expression of ATF4 target genes to complete the cellular stress response program. 

Recently, a study published in Nature Communications and by Dr. LI Xinjian's group from the Institute of Biophysics of the Chinese Academy of Sciences reported that ATF4-dependent fructolysis fuels growth of GBM.  

Researchers demonstrated that glucose deprivation markedly promotes rates of fructose metabolism in GBM by inducing mRNA and protein expression of two fructolytic genes including SLC2A5 and ALDOB. 

Mechanistically, glucose deprivation activates cellular ISR and selectively activates ATF4 translation. ATF4 induces expression of SLC2A5 and ALDOB through binding to the promoter regions of these genes, as evidenced by ATF4 ChIP-Seq analysis. Disruption of ATF4-binding DNA sequences in the promoter regions of SLC2A5 and ALDOB by gene editing can effectively inhibit ISR-induced fructose metabolism.  

Besides, functional studies demonstrated that genetically or pharmacologically blocking ISR-induced fructose metabolism significantly suppresses the fructose-mediated proliferation and clone formation of GBM cells under glucose-deprived condition. Results of mouse GBM xenograft study revealed that ISR resulted from glucose deprivation exists in GBM tissue and blocking fructose metabolism remarkedly retards GBM growth.  

These findings suggested that fructose is an alternative energy-supplying nutrient for glucose-deprived GBM. Thus, there is a caveat which concerns about the GBM patients with a high-fructose diet and developing small-molecule compounds targeting fructose metabolism may be utilized for treating human GBM.