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Protein N-glycosylation alteration and glycolysis inhibition both contribute to the antiproliferative action of 2-deoxyglucose in breast cancer cells

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Cancer cells often elicit a higher glycolytic rate than normal cells, supporting the development of glycolysis inhibitors as therapeutic agents. 2-Deoxyglucose (2-DG) is used in this context due to its ability to compete with glucose. However, many studies do not take into account that 2-DG inhibits not only glycolysis but also N-glycosylation. Since there are limited publications on 2-DG mechanism of action in breast cancer, we studied its effects in breast cancer cell lines to determine the part played by glycolysis inhibition and N-linked glycosylation interference.

Methods and Results

2-Deoxyglucose behaved as an anticancer agent with a similar efficiency on cell number decrease between the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cells. It also interfered with the N-linked glycosylation process in both cell lines as illustrated by the migration profile of the lysosomal-associated membrane protein 2 and calumenin. These results are reinforced by the appearance of an abnormal Man7GlcNAc2 structure both on lipid-linked oligosaccharides and N-linked glycoproteins of 2-DG incubated MDA-MB-231 cells. Besides, 2-DG-induced a transient endoplasmic reticulum stress that was more sustained in MDA-MB-231 cells. Both changes were abrogated by mannose. 2-DG, even in the presence of mannose, decreased glycolysis in both cell lines. Mannose partially reversed the effects of 2-DG on cell numbers with N-linked glycosylation interference accounting for 37 and 47% of 2-DG anti-cancerous effects in MDA-MB-231 and MCF-7 cells, respectively.

Conclusion

N-linked glycosylation interference and glycolysis disruption both contribute to the anticancer properties of 2-DG in breast cancer cells.

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Abbreviations

2-DG:

2-Deoxyglucose

BiP:

Binding immunoglobulin protein

CHOP:

Transcription factor CEBP homologous protein

ER:

Endoplasmic reticulum

Glc:

Glucose

GlcNAc:

N-Acetylglucosamine

IC50 :

Half maximal inhibitory concentration

IRE1:

Inositol requiring enzyme 1

LAMP2:

Lysosomal-associated membrane protein 2

LLO:

Lipid-linked oligosaccharides

Man:

Mannose

N-GP:

N-linked glycoproteins

PERK:

Pancreatic endoplasmic reticulum kinase-like endoplasmic reticulum kinase

UPR:

Unfolded protein response

XBP-1:

X-box-binding protein-1

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Funding

This project was funded by University of Lorraine and Région of Lorraine. Audrey Berthe and Claire Muller were recipient of a PhD grant of the “Ministère de l’Enseignement Supérieur et de la Recherche”.

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Authors and Affiliations

  1. Université de Lorraine, CNRS, CRAN, 54000, Nancy, France

    Audrey Berthe, Marie Zaffino, Claire Muller, Elia De Fay, Sabine Mazerbourg & Stéphane Flament

  2. Université de Lille, CNRS, UMR 8576 – UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France

    François Foulquier, Marine Houdou & Céline Schulz

  3. Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Team “Targeting Prostate Cancer cell metabolism”, 06204, Nice, France

    Frédéric Bost

  4. Faculty of Medicine, Université de Nice Sophia-Antipolis, 06204, Nice, France

    Frédéric Bost

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  1. Audrey Berthe
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  2. Marie Zaffino
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  3. Claire Muller
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Correspondence to Sabine Mazerbourg.

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Berthe, A., Zaffino, M., Muller, C. et al. Protein N-glycosylation alteration and glycolysis inhibition both contribute to the antiproliferative action of 2-deoxyglucose in breast cancer cells. Breast Cancer Res Treat 171, 581–591 (2018). https://doi.org/10.1007/s10549-018-4874-z

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