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Sci Rep. 2018 Sep 4;8(1):13190. doi: 10.1038/s41598-018-31367-9.

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway.

Author information

1
Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile. felix.urra@qf.uchile.cl.
2
Geroscience Center for Brain Health and Metabolism, Santiago, Chile. felix.urra@qf.uchile.cl.
3
Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
4
Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
5
Departamento de Química Orgánica y Físico-Química, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
6
Laboratorio de Bioinformática y Expresión Génica, INTA-Universidad de Chile, El Líbano, 5524, Santiago, Chile.
7
Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, 8380453, Chile.
8
Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Chile, Santiago, Chile.
9
Campus Río Simpson, University of Aysén, Obispo Vielmo 62, Coyhaique, 5952122, Aysén, Chile.
10
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago, Chile.
11
Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile. jcesar@u.uchile.cl.
12
Geroscience Center for Brain Health and Metabolism, Santiago, Chile. jcesar@u.uchile.cl.
13
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, 93106, United States. jcesar@u.uchile.cl.
14
The Buck Institute for Research on Aging, Novato, CA, 94945, United States. jcesar@u.uchile.cl.
15
Instituto de Química de Recursos Naturales and Programa de Investigación Asociativa en Cáncer Gástrico, Universidad de Talca, casilla 747, Talca, Chile. raraya@utalca.cl.

Abstract

Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing β1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

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