title: AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor-Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment.
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); 3295-306. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Daurio
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Tuttle
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Worth
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ethan Y
authors.initials: EY
authors.lastname: Song
authors.affiliation: SUPERS Program, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Julianne M
authors.initials: JM
authors.lastname: Davis
authors.affiliation: A.J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania. koumenis@xrt.upenn.edu.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013629:Tamoxifen; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases