Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties

Atreyi Dasgupta, Matteo Trucco, Nino Rainusso, Ronald J. Bernardi, Ryan Shuck, Lyazat Kurenbekova, David M. Loeb, Jason T. Yustein

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Ewing sarcoma (EWS) is a highly aggressive and metabolically active malignant tumor. Metabolic activity can broadly be characterized by features of glycolytic activity and oxidative phosphorylation. We have further characterized metabolic features of EWS cells to identify potential therapeutic targets. EWS cells had significantly more glycolytic activity compared to their non-malignant counterparts. Thus, metabolic inhibitors of glycolysis such as 2-deoxy-D-glucose (2DG) and of the mitochondrial respiratory pathway, such as metformin, were evaluated as potential therapeutic agents against a panel of EWS cell lines in vitro. Results indicate that 2DG alone or in combination with metformin was effective at inducing cell death in EWS cell lines. The predominant mechanism of cell death appears to be through stimulating apoptosis leading into necrosis with concomitant activation of AMPK-α. Furthermore, we demonstrate that the use of metabolic modulators can target putative EWS stem cells, both in vitro and in vivo, and potentially overcome chemotherapeutic resistance in EWS. Based on these data, clinical strategies using drugs targeting tumor cell metabolism present a viable therapeutic modality against EWS.

Original languageEnglish (US)
Pages (from-to)77292-77308
Number of pages17
JournalOncotarget
Volume8
Issue number44
DOIs
StatePublished - Jan 1 2017

Keywords

  • 2DG
  • Cancer stem cells
  • Ewing sarcoma
  • Metabolism
  • Metformin

ASJC Scopus subject areas

  • Oncology

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    Dasgupta, A., Trucco, M., Rainusso, N., Bernardi, R. J., Shuck, R., Kurenbekova, L., Loeb, D. M., & Yustein, J. T. (2017). Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties. Oncotarget, 8(44), 77292-77308. https://doi.org/10.18632/oncotarget.20467