Oncotarget

Research Papers:

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 and Jason T. Yustein _

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Oncotarget. 2017; 8:77292-77308. https://doi.org/10.18632/oncotarget.20467

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Abstract

Atreyi Dasgupta1, Matteo Trucco2, Nino Rainusso1, Ronald J. Bernardi1, Ryan Shuck1, Lyazat Kurenbekova1, David M. Loeb3 and Jason T. Yustein1,4,5

1The Faris D. Virani Ewing Sarcoma Center at The Texas Children’s Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA

2Sylvester Comprehensive Cancer Center, Department of Pediatrics, Hematology-Oncology, University of Miami-Miller School of Medicine, Miami, FL 33136, USA

3Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD 21231, USA

4Integrative Molecular and Biological Sciences Program, Baylor College of Medicine, Houston, TX 77030, USA

5Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA

Correspondence to:

Jason T. Yustein, email: [email protected]

Keywords: metabolism, cancer stem cells, Ewing sarcoma, 2DG, metformin

Received: March 21, 2017     Accepted: July 20, 2017     Published: August 24, 2017

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.


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