Original Articles: Basic ScienceExploring metabolic reprogramming in melanoma via acquired resistance to the oxidative phosphorylation inhibitor phenforminPistoni, Mariaelenaa,,*; Tondelli, Giuliaa,,*; Gallo, Cristinaa; Torricelli, Federicaa; Maresca, Alessandrab; Carelli, Valeriob,,c; Ciarrocchi, Alessiaa; Dallaglio, KatiusciaaAuthor Information aLaboratory of Translational Research, Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia bIRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital cDepartment of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy *Dr. Mariaelena Pistoni and Dr. Giulia Tondelli contributed equally to the writing of this article. Received 27 November 2018 Accepted 7 May 2019 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.melanomaresearch.com. Correspondence to Katiuscia Dallaglio, PhD, Laboratory of Translational Research, Azienda USL – Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Viale Risorgimento n.80, 42123 Reggio Emilia, Italy, E-mail: [email protected] Melanoma Research: February 2020 - Volume 30 - Issue 1 - p 1-13 doi: 10.1097/CMR.0000000000000624 Buy SDC Metrics Abstract Therapeutic failures in cancer therapy are often associated with metabolic plasticity. The use of metabolic modulators as anti-cancer agents has been effective in correcting metabolic alterations; however, molecular events behind metabolic switch are still largely unexplored. Herein, we characterize the molecular and functional events that follow prolonged oxidative phosphorylation inhibition by phenformin in order to study how melanoma cells adapt to this specific metabolic pressure. We show that melanoma cells cultured up to 3 months with high doses of phenformin (R-cells) are less viable and migrate and invade less than parental (S-) cells. Microarray analysis of R-melanoma cells reveals a switch in the energy production strategy accompanied by the modulation of several immunological-associated genes. R-cells display low oxygen consumption rate and high basal extracellular acidification rate. When treated with vemurafenib, R-cell viability, growth and extracellular signal-regulated kinase activation decrease. Finally, phenformin withdrawal reverts R-cells phenotype. In summary, our study provides an in vitro model of on-off metabolic switch in melanoma and reveals interesting molecular signatures controlling metabolic reprogramming in this tumour. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.