title: A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth.
abstract: The glucose analogue 2-deoxy-D-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose catabolism. In addition, 2-DG provoked similar concentration changes of sugar-phosphate intermediates in wild-type and 2-DG-resistant yeast strains and in human primary fibroblasts. Finally, a genome-wide analysis revealed 19 2-DG-resistant yeast knockouts of genes implicated in carbohydrate metabolism and mitochondrial homeostasis, as well as ribosome biogenesis, mRNA decay, transcriptional regulation, and cell cycle. Thus, processes beyond the metabolic block are essential for the biological properties of 2-DG.
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany. ralser@molgen.mpg.de
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
authors.forename: Mirjam M
authors.initials: MM
authors.lastname: Wamelink
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Christian
authors.initials: C
authors.lastname: Joppich
authors.forename: Sylvia
authors.initials: S
authors.lastname: Krobitsch
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000494:pharmacology*; D005057:Eukaryotic Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects
chemical_list: D003847:Deoxyglucose