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

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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.

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Acknowledgments

The authors would like to thank Jenette Shoeneman, Laura Chubb, Dr. Scott Hafeman, and Dr. Jessica Cantrell for assistance with the animal experiments, Polly Webb for assistance with lactate measurements, Dr. David Siegel (University of Colorado Health Sciences Center) for his help in performing the oxygen utilization experiments, and Dr. Daniel Gustafson for critical manuscript review. This work was supported by the Colorado State University Supercluster and the estate of Mr. Jeffery Harbers.

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The authors declare they have no conflicts of interest.

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Authors and Affiliations

  1. Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, CO, 80523-1620, USA

    Joseph L. Sottnik, Janet C. Lori, Barbara J. Rose & Douglas H. Thamm

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  1. Joseph L. Sottnik
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  2. Janet C. Lori
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  3. Barbara J. Rose
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Correspondence to Douglas H. Thamm.

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10585_2011_9417_MOESM1_ESM.tiff

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

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)

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Sottnik, J.L., Lori, J.C., Rose, B.J. et al. Glycolysis inhibition by 2-deoxy-d-glucose reverts the metastatic phenotype in vitro and in vivo. Clin Exp Metastasis 28, 865–875 (2011). https://doi.org/10.1007/s10585-011-9417-5

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