Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 1, pp 251–262

Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells

  • Huaping Liu
  • Metin Kurtoglu
  • Yenong Cao
  • Haibin Xi
  • Rakesh Kumar
  • Jeffrey M. Axten
  • Theodore J. Lampidis
Original Article

DOI: 10.1007/s00280-013-2193-y

Cite this article as:
Liu, H., Kurtoglu, M., Cao, Y. et al. Cancer Chemother Pharmacol (2013) 72: 251. doi:10.1007/s00280-013-2193-y



Inhibition of glucose metabolism has recently become an attractive target for cancer treatment. Accordingly, since 2-deoxyglucose (2-DG) competes effectively with glucose, it has come under increasing scrutiny as a therapeutic agent. The initial response of tumor cells to 2-DG is growth inhibition, which is thought to conserve energy and consequently protect cells from its ATP-lowering effects as a glycolytic inhibitor. However, since 2-DG also mimics mannose and thereby interferes with N-linked glycosylation, the question is raised of how this sugar analog inhibits tumor cell growth and whether the mechanism by which it protects cells can be manipulated to convert 2-DG-induced growth inhibition to cell death.


Cell growth and death were measured via counting viable and dead cells based on trypan blue exclusion. Markers of ATP reduction and the unfolded protein response (UPR) were detected by Western blot. Protein functions were manipulated through chemical compounds, siRNA and the use of gene-specific wild-type and knock-out mouse embryonic fibroblasts (MEFs).


At 2-DG concentrations that can be achieved in human plasma without causing significant side effects, we find (a) It induces growth inhibition predominantly by interference with glycosylation, which leads to accumulation of unfolded proteins in the endoplasmic reticulum activating the UPR; (b) Inhibition of PERK (but not ATF6 or IRE1), a major component of the UPR, leads to conversion of 2-DG-induced growth inhibition to cell death and (c) secondarily to PERK, inhibition of GCN2, a kinase that is activated in response to low intracellular glutamine, increases 2-DG’s cytotoxic effects in PERK −/− MEFs.


Overall, these findings present a novel anticancer strategy that can be translated into therapeutic gain as they uncover the metabolic target PERK, and to a lesser degree GCN2, that when inhibited convert 2-DG’s static effect to a toxic one in tumor cells growing under normoxia.


2-Deoxyglucose Endoplasmic reticulum stress Unfolded protein response PERK GCN2 





Unfolded protein response


Mouse embryonic fibroblast


AMP-activated protein kinase


Endoplasmic reticulum


Pentose phosphate shunt


Reactive oxygen species

Supplementary material

280_2013_2193_MOESM1_ESM.pdf (244 kb)
Supplementary material 1 (PDF 243 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Huaping Liu
    • 1
  • Metin Kurtoglu
    • 1
  • Yenong Cao
    • 2
  • Haibin Xi
    • 3
    • 6
  • Rakesh Kumar
    • 4
  • Jeffrey M. Axten
    • 5
  • Theodore J. Lampidis
    • 1
  1. 1.Department of Cell Biology and Sylvester Comprehensive Cancer CenterUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Department of Molecular and Cellular PharmacologyUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Sheila and David Fuente Graduate Program in Cancer BiologyUniversity of Miami Miller School of MedicineMiamiUSA
  4. 4.BiologyGlaxoSmithKlineCollegevilleUSA
  5. 5.Medicinal Chemistry, Protein Dynamics DPUGlaxoSmithKlineCollegevilleUSA
  6. 6.Department of Molecular, Cell and Developmental BiologyUniversity of California, Los AngelesLos AngelesUSA

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