title: Novel actions of 2-deoxy-D-glucose: protection against Shiga toxins and changes in cellular lipids.
abstract: 2-Deoxy-D-glucose (2DG) is a structural analogue of glucose with well-established applications as an inhibitor of glycolysis and N-glycosylation. Importantly, 2DG has been shown to improve the efficacy of several cancer chemotherapeutic agents in vivo and thus it is in clinical studies in combination with chemotherapy and radiotherapy. However, although 2DG has been demonstrated to modulate many cellular functions, including autophagy, apoptosis and cell cycle control, little is known about the effects of 2DG on intracellular transport, which is of great importance when predicting the effects of 2DG on therapeutic agents. In addition to proteins, lipids play important roles in cellular signalling and in controlling cellular trafficking. We have, in the present study, investigated the effects of 2DG on cellular lipid composition and by use of protein toxins we have studied 2DG-mediated changes in intracellular trafficking. By quantifying more than 200 individual lipid species from 17 different lipid classes, we have found that 2DG treatment changes the levels and/or species composition of several lipids, such as phosphatidylinositol (PI), diacylglycerol (DAG), cholesteryl ester (CE), ceramide (Cer) and lysophospho-lipids. Moreover, 2DG becomes incorporated into the carbohydrate moiety of glycosphingolipids (GSLs). In addition, we have discovered that 2DG protects cells against Shiga toxins (Stxs) and inhibits release of the cytotoxic StxA1 moiety in the endoplasmic reticulum (ER). 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 by 2DG. In conclusion, our results reveal novel actions of 2DG on cellular lipids and Stx toxicity.
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Simona
authors.initials: S
authors.lastname: Kavaliauskiene
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
authors.forename: Tore
authors.initials: T
authors.lastname: Skotland
authors.affiliation: Zora Biosciences, 02150 Espoo, Finland.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Sylvänne
authors.affiliation: Zora Biosciences, 02150 Espoo, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Simolin
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
authors.forename: Tove Irene
authors.initials: TI
authors.lastname: Klokk
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
authors.forename: Maria Lyngaas
authors.initials: ML
authors.lastname: Torgersen
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
authors.forename: Anne Berit Dyve
authors.initials: AB
authors.lastname: Lingelem
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
authors.forename: Roger
authors.initials: R
authors.lastname: Simm
authors.affiliation: Zora Biosciences, 02150 Espoo, Finland.
authors.forename: Kim
authors.initials: K
authors.lastname: Ekroos
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway kirsten.sandvig@ibv.uio.no.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sandvig
mesh_terms: D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D003847:Deoxyglucose / Q000494:pharmacology*; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism*; D022603:Shiga Toxins / Q000633:toxicity*
chemical_list: D008563:Membrane Lipids; D022603:Shiga Toxins; D003847:Deoxyglucose
keywords: Shiga toxin; endoplasmic reticulum (ER); globotriaosylceramide; intracellular transport; lipidomics