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Therapeutics, Targets, and Chemical Biology

AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment

Natalie A. Daurio, Stephen W. Tuttle, Andrew J. Worth, Ethan Y. Song, Julianne M. Davis, Nathaniel W. Snyder, Ian A. Blair and Constantinos Koumenis
Natalie A. Daurio
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Stephen W. Tuttle
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Andrew J. Worth
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Ethan Y. Song
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Julianne M. Davis
SUPERS Program, University of Pennsylvania, Philadelphia, Pennsylvania.
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Nathaniel W. Snyder
A.J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania.
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Ian A. Blair
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Constantinos Koumenis
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
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  • For correspondence: koumenis@xrt.upenn.edu
DOI: 10.1158/0008-5472.CAN-15-2197
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Abstract

Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER)–positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacologic and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMP-activated protein kinase (AMPK) signaling pathway in vitro and in vivo. AMPK in turn promotes glycolysis and alters fatty acid metabolism. We also show that tamoxifen-induced cytotoxicity is modulated by isoform-specific effects of AMPK signaling, in which AMPKα1 promotes cell death through inhibition of the mTOR pathway and translation. By using agents that concurrently target distinct adaptive responses to tamoxifen-mediated metabolic reprogramming, we demonstrate increased cytotoxicity through synergistic therapeutic approaches. Our results demonstrate novel metabolic perturbations by tamoxifen in tumor cells, which can be exploited to expand the therapeutic potential of tamoxifen treatment beyond ER+ breast cancer. Cancer Res; 76(11); 1–12. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received August 13, 2015.
  • Revision received February 26, 2016.
  • Accepted March 14, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst May 20, 2016
doi: 10.1158/0008-5472.CAN-15-2197

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AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment
Natalie A. Daurio, Stephen W. Tuttle, Andrew J. Worth, Ethan Y. Song, Julianne M. Davis, Nathaniel W. Snyder, Ian A. Blair and Constantinos Koumenis
Cancer Res May 20 2016 DOI: 10.1158/0008-5472.CAN-15-2197

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AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment
Natalie A. Daurio, Stephen W. Tuttle, Andrew J. Worth, Ethan Y. Song, Julianne M. Davis, Nathaniel W. Snyder, Ian A. Blair and Constantinos Koumenis
Cancer Res May 20 2016 DOI: 10.1158/0008-5472.CAN-15-2197
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Cancer Research Online ISSN: 1538-7445
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