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Breast Cancer Research and Treatment

, Volume 171, Issue 3, pp 581–591 | Cite as

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

  • Audrey Berthe
  • Marie Zaffino
  • Claire Muller
  • François Foulquier
  • Marine Houdou
  • Céline Schulz
  • Frédéric Bost
  • Elia De Fay
  • Sabine Mazerbourg
  • Stéphane Flament
Preclinical study

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.

Keywords

Breast cancer 2-Deoxyglucose Glycolysis N-Glycosylation Endoplasmic reticulum stress 

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

Notes

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”.

Compliance with ethical standards

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Audrey Berthe
    • 1
  • Marie Zaffino
    • 1
  • Claire Muller
    • 1
  • François Foulquier
    • 2
  • Marine Houdou
    • 2
  • Céline Schulz
    • 2
  • Frédéric Bost
    • 3
    • 4
  • Elia De Fay
    • 1
  • Sabine Mazerbourg
    • 1
  • Stéphane Flament
    • 1
  1. 1.Université de Lorraine, CNRS, CRANNancyFrance
  2. 2.Université de Lille, CNRS, UMR 8576 – UGSF - Unité de Glycobiologie Structurale et FonctionnelleLilleFrance
  3. 3.Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Team “Targeting Prostate Cancer cell metabolism”NiceFrance
  4. 4.Faculty of MedicineUniversité de Nice Sophia-AntipolisNiceFrance

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