The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor 2-deoxyglucose
@article{Defenouillre2019TheIO, title={The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor 2-deoxyglucose}, author={Quentin Defenouill{\`e}re and Agathe Verraes and Clotilde Laussel and Anne Friedrich and Joseph Schacherer and S{\'e}bastien L{\'e}on}, journal={Science Signaling}, year={2019}, volume={12} }
An evolutionarily conserved family of phosphatases enables cells to resist the toxic metabolic effects of 2-deoxyglucose. Resisting a metabolic poison Once imported into cells and phosphorylated, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, leading to the proposal of using 2DG as a cancer treatment. Using yeast as a model, Defenouillère et al. investigated how cells become resistant to 2DG. Exposure to 2DG activated several signaling pathways that resulted in the increased…
14 Citations
Cellular toxicity of the metabolic inhibitor 2-deoxyglucose and associated resistance mechanisms.
- BiologyBiochemical pharmacology
- 2020
Spontaneous mutations that confer resistance to 2-deoxyglucose act through Hxk2 and Snf1 pathways to regulate gene expression and HXT endocytosis
- BiologyPLoS genetics
- 2020
Genetic studies of 2DG resistance using the dominant SNF1-G53R allele in cells that are genetically compromised in both the endocytosis and DOG pathways suggest that at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.
2-deoxyglucose inhibits yeast AMPK signaling and triggers glucose transporter endocytosis, potentiating the drug toxicity
- Biology, ChemistrybioRxiv
- 2022
It is shown that 2DG-induced endocytosis is detrimental to cells, and the lack of Rod1 counteracts this process by stabilizing glucose transporters at the plasma membrane, and a remarkable strategy to bypass 2DDG toxicity involving glucose transporter regulation is highlighted.
Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics
- Biology, ChemistryPLoS computational biology
- 2022
A genetic screen in Saccharomyces cerevisiae generated a novel spontaneous mutation in hexokinase-2, hxk2G238V, that confers resistance to the toxic glucose analog 2-deoxyglucose (2DG), providing insights that may apply to cancer biology and drug resistance.
Spontaneous mutations that confer resistance to 2-deoxyglucose act through Hxk2 and Snf1 pathways to regulate gene expression and HXT endocytosis
- BiologybioRxiv
- 2019
Bakers’ yeast is used as a model organism to better understand the mechanism of toxicity and acquisition of resistance to 2-deoxyglucose and it is concluded that Snf1 kinase-mediated regulation of the endocytosis of the hexose transporters and regulation of DOG2 expression are important mechanisms for resistance to this glucose analog.
‘Sugarcoating’ 2-deoxyglucose: mechanisms that suppress its toxic effects
- BiologyCurrent genetics
- 2020
The cellular and metabolic pathways that play a role in 2-deoxyglucose sensitivity are reviewed and how the modifications to these pathways result in acquisition of 2- deoxyglUCose resistance are discussed.
Drug resistance in diploid yeast is acquired through dominant alleles, haploinsufficiency, gene duplication and aneuploidy
- BiologyPLoS genetics
- 2021
The frequent use of aneuploidy as a genetic strategy for drug resistance in diploid yeast and human tumors may be in part due to its potential for reversibility when selection pressure shifts.
Glycolysis inhibition and apoptosis induction in human prostate cancer cells by FV-429-mediated regulation of AR-AKT-HK2 signaling network.
- Biology, ChemistryFood and chemical toxicology : an international journal published for the British Industrial Biological Research Association
- 2020
2-Deoxy-d-glucose: from diagnostics to therapeutics
- Biology, Medicine
- 2021
The diagnostic and therapeutic potentials of 2-deoxy-glucose are reviewed with special emphasis on to its implications in SARS-CoV-2.
Phosphorylation of the GARP Subunit Vps53 by Snf1 Leads to the Formation of a Golgi – Mitochondria Contact Site (GoMiCS) in Yeast
- BiologybioRxiv
- 2020
The GARP subunit Vps53 is both an in vivo and in vitro target of Snf1 and phosphorylation depends on the nature and quantity of the available carbon source, which results in altered mitochondrial dynamics and the formation of a previously unknown contact site between the Golgi apparatus and mitochondria, termed GoMiCS.
References
SHOWING 1-10 OF 138 REFERENCES
Genetic Analysis of Resistance and Sensitivity to 2-Deoxyglucose in Saccharomyces cerevisiae
- Biology, Computer ScienceGenetics
- 2014
It is shown that the relative toxicity of 2-deoxyglucose is carbon source dependent, as is the resistance conferred by gene deletions, and that these newly identified genes do not in fact confer significant resistance to 2- deoxyglUCose.
A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth
- BiologyProceedings of the National Academy of Sciences
- 2008
It is reported that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG, indicating that 2- DG does not block cell growth solely by preventing glucose catabolism and processes beyond the metabolic block are essential for the biological properties of 2-G.
Novel actions of 2-deoxy-D-glucose: protection against Shiga toxins and changes in cellular lipids.
- Biology, ChemistryThe Biochemical journal
- 2015
The data indicate that the 2DG-induced protection against Stx is independent of inhibition of glycolysis or N-glycosylation, but rather mediated via the depletion of Ca(2+) from cellular reservoirs by2DG.
2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy.
- Biology, ChemistryCancer letters
- 2014
Identification of Mitogen-Activated Protein Kinase Signaling Pathways That Confer Resistance to Endoplasmic Reticulum Stress in Saccharomyces cerevisiae
- BiologyMolecular Cancer Research
- 2005
The feasibility of using the yeast deletion pool to identify relevant mammalian orthologues of the UPR is shown, and it is proposed that the SLT2 MAPK pathway is an important cell survival signaling pathway during ER stress.
Cooperative Regulation of DOG2, Encoding 2-Deoxyglucose-6-Phosphate Phosphatase, by Snf1 Kinase and the High-Osmolarity Glycerol–Mitogen-Activated Protein Kinase Cascade in Stress Responses of Saccharomyces cerevisiae
- BiologyJournal of bacteriology
- 2000
The results suggest that Snf1p kinase and the high-osmolarity glycerol-mitogen-activated protein kinase cascade are likely to be involved in the signaling pathway of oxidative stress and osmotic stress in regulation of DOG2.
The Warburg and Crabtree effects: On the origin of cancer cell energy metabolism and of yeast glucose repression.
- BiologyBiochimica et biophysica acta
- 2011
Characterization of a phosphatase specific for 2‐deoxyglucose‐6‐phosphate in a yeast mutant
- Biology, ChemistryFEBS letters
- 1977
Studies on the mechanism of resistance to 2-deoxy-D-glucose in mammalian cell cultures.
- BiologyThe Journal of biological chemistry
- 1962
Transcriptional control of nonfermentative metabolism in the yeast Saccharomyces cerevisiae
- BiologyCurrent Genetics
- 2003
This review summarizes regulatory cis-acting elements of structural genes of the nonfermentative metabolism, together with the corresponding DNA-binding proteins, and describes the molecular interactions among general regulators and pathway-specific factors.