Logo image
Back
AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor-Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment
Journal article   Open access   Peer reviewed

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 research (Chicago, Ill.), v 76(11), pp 3295-3306
01 Jun 2016
DOI: https://doi.org/10.1158/0008-5472.CAN-15-2197
PMID: 27020861
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/0008-5472.can-15-2197View
Accepted (AM)Open Access (License Unspecified),  Open
url
https://doi.org/10.1158/0008-5472.CAN-15-2197View
Published, Version of Record (VoR) Open

Abstract

AMP-Activated Protein Kinases - metabolism Animals Antineoplastic Agents, Hormonal - pharmacology Apoptosis - drug effects Blotting, Western Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Proliferation - drug effects Female Gene Expression Regulation, Neoplastic - drug effects Glycolysis - drug effects Humans Mice Mice, Nude Mitochondria, Liver - drug effects Mitochondria, Liver - metabolism Oxygen Consumption - drug effects Phosphorylation - drug effects Proto-Oncogene Proteins c-akt - metabolism Receptors, Estrogen - metabolism Signal Transduction - drug effects Tamoxifen - pharmacology TOR Serine-Threonine Kinases - metabolism Tumor Cells, Cultured
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); 3295-306. ©2016 AACR.

Metrics

14 Record Views
79 citations in Web of Science
83 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
Logo image