ATF4-dependent fructolysis fuels growth of glioblastoma multiforme

Excessive consumption of fructose contributes to cancer development, but the underlying mechanisms are poorly understood. Here, the authors show that glucose deprivation induces fructolysis through selective activation of ATF4 translation, thereby supporting malignant progression of human glioblastoma. Excessive consumption of fructose in the Western diet contributes to cancer development. However, it is still unclear how cancer cells coordinate glucose and fructose metabolism during tumor malignant progression. We demonstrate here that glioblastoma multiforme (GBM) cells switch their energy supply from glycolysis to fructolysis in response to glucose deprivation. Mechanistically, glucose deprivation induces expression of two essential fructolytic proteins GLUT5 and ALDOB through selectively activating translation of activating transcription factor 4 (ATF4). Functionally, genetic or pharmacological disruption of ATF4-dependent fructolysis significantly inhibits growth and colony formation of GBM cells in vitro and GBM growth in vivo. In addition, ATF4, GLUT5, and ALDOB levels positively correlate with each other in GBM specimens and are poor prognostic indicators in GBM patients. This work highlights ATF4-dependent fructolysis as a metabolic feature and a potential therapeutic target for GBM.

Automated summary

Excessive consumption of fructose contributes to cancer development. This study reveals that glucose deprivation induces fructolysis in glioblastoma cells, which is mediated by ATF4. Inhibition of ATF4-dependent fructolysis significantly suppresses growth and colony formation of glioblastoma cells in vitro and in vivo.