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Glucose metabolism and hexosamine pathway regulate oncogene-induced senescence
D Gitenay1, C Wiel1, H Lallet-Daher1
11] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France [2] CNRS UMR5286, Lyon, France [3] Centre Léon Bérard, Lyon, France [4] Université de Lyon, Lyon, France.
Abstract:
Oncogenic stress-induced senescence (OIS) prevents the ability of oncogenic signals to induce tumorigenesis. It is now largely admitted that the mitogenic effect of oncogenes requires metabolic adaptations to respond to new energetic and bio constituent needs. Yet, whether glucose metabolism affects OIS response is largely unknown. This is largely because of the fact that most of the OIS cellular models are cultivated in glucose excess. In this study, we used human epithelial cells, cultivated without glucose excess, to study alteration and functional role of glucose metabolism during OIS. We report a slowdown of glucose uptake and metabolism during OIS. Increasing glucose metabolism by expressing hexokinase2 (HK2), which converts glucose to glucose-6-phosphate (G6P), favors escape from OIS. Inversely, expressing a glucose-6-phosphatase, [corrected] pharmacological inhibition of HK2, or adding nonmetabolizable glucose induced a premature senescence. Manipulations of various metabolites covering G6P downstream pathways (hexosamine, glycolysis, and pentose phosphate pathways) suggest an unexpected role of the hexosamine pathway in controlling OIS. Altogether, our results show that decreased glucose metabolism occurs during and participates to OIS.
Insights
Oncogenic stress-induced senescence (OIS) involves altered glucose metabolism. Decreased glucose uptake and metabolism promote OIS, while enhancing it helps cells escape senescence, revealing a key role for glucose metabolism in cancer prevention.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Cancer Research
Background:
- Oncogenic stress-induced senescence (OIS) is a tumor suppression mechanism.
- Metabolic adaptations are crucial for oncogene-driven proliferation.
- The role of glucose metabolism in OIS remains largely unexplored, especially in non-excessive glucose conditions.
Purpose of the Study:
- To investigate the alterations and functional significance of glucose metabolism during OIS in human epithelial cells.
- To determine how modulating glucose metabolism impacts OIS progression and escape.
Main Methods:
- Cultivation of human epithelial cells under conditions without glucose excess.
- Analysis of glucose uptake and metabolism during OIS.
- Genetic manipulation of key glucose metabolism enzymes (hexokinase 2, glucose-6-phosphatase).
- Pharmacological inhibition of hexokinase 2.
- Assessment of OIS and senescence escape following metabolic alterations.
Main Results:
- A significant slowdown in glucose uptake and metabolism was observed during OIS.
- Overexpression of hexokinase 2 (HK2) promoted escape from OIS.
- Inhibition of HK2 or use of non-metabolizable glucose induced premature senescence.
- The hexosamine pathway emerged as a critical regulator of OIS.
Conclusions:
- Decreased glucose metabolism is a characteristic feature of OIS.
- Modulating glucose metabolism, particularly the hexosamine pathway, influences the OIS outcome.
- Glucose metabolism plays a functional role in the OIS process, impacting tumor suppression.
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