Aerobic respiration is the major way of metabolism for normal cells, while the cancer cells choose glycolysis, a type with low efficiency and involving no oxygen even when oxygen is sufficient. Cancer cells tend to assimilate an abundance of glucose and extracellular glutamine to make up for their energy source. Metabolism of glutamine is also intimately involved in the cells’ redox homeostasis.

Prof. WU Mian, Prof. LIU Lianxin from Hefei National Laboratory for Physical Science at the Microscale, and Prof. ZHANG Qingyuan from Harbin Medical University Cancer Hospital worked on how cancer cells balance glycolysis and oxidative phosphorylation during glutamine deprivation. This study was published on Advanced science.

The heightened utilization and limited circulation of blood leave cancer cells frequently in an environment short of glutamine, where cancer cells consequently mount adaptive responses like autophagy, inhibition protein synthesis and proliferation, and metabolic reprogramming to maintain their survival.

In this study, the researchers found that the protein and transcription factor, DNA damage induced transcript 3 (DDIT3) plays a crucial role in the reprogramming responses. Typically, DDIT3 is triggered by hostile environment including DNA damage, starvation and shortage of oxygen.

This transcription factor prompt glycolysis by inhibiting the negative glycolytic regulator and restraining mitochondrial respiration to reduce noxious reactive oxygen species. It therefore allows the cancer cells to survival via these adaptive responses.

How DDIT3 prompt glycolysis and restrain mitochondrial respiration. (Image by LI Mingyue et al.)

To have a deeper insight into the mechanism of the metabolic reprogramming responses during glutamine deprivation, RNA sequencing analyses were undertaken in hepatocellular carcinoma (HepG2) cells cultured with or without glutamine. Genes with changes of expressions, among which DDIT3 was also listed, are supposed to be related to the process of suppression response. These related genes were individually knocked down to observe their behavior during glutamine deprivation, and the results confirmed that DDIT3’s capacity in prompting glycolysis provide tangible benefits for cancer cells.

The study showed how DDIT3 help cancer cells better survive in an unfavorable environment and achieved a better knowledge of the respirational mechanism of cancer cells. The consequences in the research may shed light on future cancer treatment.

Paper link:

http://doi.org/10.1002/advs.202003732

(Written by MIAO Xinyi, edited by JIANG Pengcen, USTC News Center)