Clinical & Experimental Metastasis

, Volume 28, Issue 8, pp 865–875

Glycolysis inhibition by 2-deoxy-d-glucose reverts the metastatic phenotype in vitro and in vivo

  • Joseph L. Sottnik
  • Janet C. Lori
  • Barbara J. Rose
  • Douglas H. Thamm
Research Paper

DOI: 10.1007/s10585-011-9417-5

Cite this article as:
Sottnik, J.L., Lori, J.C., Rose, B.J. et al. Clin Exp Metastasis (2011) 28: 865. doi:10.1007/s10585-011-9417-5

Abstract

Metastasis is the primary cause of death from many tumors, and novel anti-metastatic therapies are necessary. Recently, we showed that metastatic tumors down-regulate key oxidative phosphorylation (OXPHOS) genes in favor of glycolysis, a further enhancement of the Warburg effect. Therefore, we sought to determine if restriction of glycolysis using 2-deoxy-d-glucose (2DG) would lead to increased utilization of OXPHOS and inhibition of the metastatic phenotype. Noncytotoxic concentrations of 2DG dose-dependently inhibited in vitro migration and invasion in the highly metastatic DLM8-luc-M1 osteosarcoma (OS) cell line, as well as other metastatic human, canine, and murine cancer cells of different histotypes. This was associated with cytoskeletal rearrangement and inhibition of cathepsin L expression. A dose-dependent shift toward OXPHOS was confirmed by demonstrating increased oxygen utilization and decreased lactate production in 2DG treated cells. Finally, 2DG treatment significantly delayed metastasis and prolonged survival in an orthotopic postsurgical OS model. In conclusion, this work suggests that forcing cells away from glycolysis may inhibit key components of the metastatic phenotype, providing a novel avenue for metastasis prevention.

Keywords

Mouse Metabolism Oxidative phosphorylation Invasion 

Supplementary material

10585_2011_9417_MOESM1_ESM.tiff (5.6 mb)
Supplemental Fig. 1: 2DG does not significantly impact clonogenic cell growth. DLM8-Luc-M1 cells were treated with varying concentrations of 2DG for 24 h, followed by plating in 10 cm dishes. Colonies were stained with crystal violet and counted manually. There was no significant difference in colony formation upon 2DG exposure. Error bars indicate standard deviation. (TIFF 5691 kb)
10585_2011_9417_MOESM2_ESM.tif (5.3 mb)
Supplemental Fig. 2: 2DG does not significantly impact cell luminosity.a DLM8-luc-M1 cells were treated with varying concentrations of 2DG before the addition of luciferin and determination of photon flux. Each condition was analyzed in triplicate and mean ± SD depicted. Mice were challenged subcutaneously with DLM8-luc-M1 tumor cells. Once the mean tumor diameter was 5 mm, treatment with 2DG was initiated. b No significant inhibition of tumor cross-sectional area was observed. Tumor bioluminescence was measured to determine if 2DG inhibited photon flux. c There was no significant difference in tumor bioluminescence when normalized by tumor cross-sectional area. (TIFF 5465 kb)

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Joseph L. Sottnik
    • 1
  • Janet C. Lori
    • 1
  • Barbara J. Rose
    • 1
  • Douglas H. Thamm
    • 1
  1. 1.Animal Cancer Center, Department of Clinical SciencesColorado State UniversityFort CollinsUSA