MRC National Institute for Medical Research, London
Science for Health
Mariia Yuneva group project:
The role of glucose and glutamine metabolism in MYC-induced tumorigenesis
MYC proto-oncogene is involved in the genesis of multiple human cancers. MYC encodes a transcriptional factor that regulates the expression of multiple genes involved in cell proliferation, differentiation, growth and cell death. MYC is also a major regulator of cellular metabolism.
Our recent work demonstrated that MYC-induced liver tumours have increased catabolism of glucose into lactate and both increased glucose and increased glutamine catabolism through the Krebs cycle. Increased glucose and glutamine catabolism in MYC-induced liver tumors is associated with the expression of regulatory enzyme isoforms distinct from the ones expressed in normal liver. MYC-induced liver tumours switch from glucokinase to hexokinase II (Hk2) to regulate the first step of glycolysis and from liver glutaminase (Gls2) to kidney glutaminase (Gls1) to regulate the first step of glutamine catabolism. Even though placed in a tissue-specific context, the pattern of metabolic enzyme isoforms found in MYC-induced liver tumors is also observed in MYC-induced lung tumors (Figure 2).
Figure 2
Click image to view at full-size
Metabolism of tumors can be determined by the initiating lesion and tissue of origin. MYC-induced liver tumors have increased glucose catabolism into lactate. They also have increased catabolism of both glucose and glutamine through the Krebs cycle. In contrast, MET-induced liver tumors do not have increased lactate production and have increased glutamine synthesis. Increased glucose and glutamine catabolism in MYC-induced liver tumors is associated with the expression of Hk2 hexokinase and Gls1 glutaminase isoforms. In MYC-induced lung tumors increased expression of Gls1 glutaminase is combined with increased expression of glutamine synthetase (GLUL), the enzyme responsible for the synthesis of glutamine from glutamate, suggesting that MYC-induced lung tumors can both consume and produce glutamine.
Our experiments in vitro demonstrated that cells with increased expression of MYC are sensitive to glutamine deprivation (Figure 2) and inhibition of Gls1 expression and activity suggesting that Gls1 and glutamine metabolism can be plausible targets for the therapy of tumors with disregulated MYC activity.
We are employing transgenic mouse models as well as RNA interference (RNAi) technology to manipulate the expression of Hk2 and Gls1 in a tissue-specific manner. The goal is to evaluate the requirement of these specific enzyme isoforms and pathways of glucose and glutamine metabolism that they regulate, for various stages of MYC-induced tumorigenesis in different tissues. We are also interested in identifying novel metabolic pathways that may be required for MYC-induced tumorigenesis and can be exploited as potential therapeutic targets.
Figure 3
Click image to view at full-size
Cells with induced activity of MYC oncogene (MYCOn) die by apoptosis in the absence of glutamine. In the bottom panel cells that have nuclei with apoptotic morphology (fragmented or condensed) are indicated by arrows.
Yuneva group
Recent publications
Research projects
- The role of glucose and glutamine metabolism in MYC-induced tumorigenesis
- Employing mouse models to evaluate the relationship between genetic lesions, tumor metabolism and tumor environment
- Evaluating the relationship between genetic lesions and metabolic changes in human cancers
Yuneva biography
© MRC National Institute for Medical Research
The Ridgeway, Mill Hill, London NW7 1AA
Top of page