A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth.
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.
Ralser
Markus
M
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany. ralser@molgen.mpg.de
Wamelink
Mirjam M
MM
Struys
Eduard A
EA
Joppich
Christian
C
Krobitsch
Sylvia
S
Jakobs
Cornelis
C
Lehrach
Hans
H
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
D003847:Deoxyglucose