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A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth

Author:
Ralser, Markus, Wamelink, Mirjam M., Struys, Eduard A., Joppich, Christian, Krobitsch, Sylvia, Jakobs, Cornelis, Lehrach, Hans
Source:
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.46 pp. 17807-17811
ISSN:
0027-8424
Subject:
biogenesis, cell cycle, cell growth, fibroblasts, genes, glucose, glycolysis, homeostasis, humans, longevity, low calorie diet, messenger RNA, metabolic studies, neoplasms, neurodegenerative diseases, pentose phosphate cycle, ribosomes, transcription (genetics), yeasts
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.
Agid:
2362175