https://phaidra.vetmeduni.ac.at/o:2513 The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation Baier, Dina Dina Baier Medical University Vienna / University of Vienna Berger, Walter Walter Berger 0000-0003-0014-1658 Medical University Vienna Keppler, Bernhard K. Bernhard K. Keppler University of Vienna Koellensperger, Gunda Gunda Koellensperger University of Vienna Meier-Menches, Samuel M. Samuel M. Meier-Menches University of Vienna / Medical University of Vienna Heffeter, Petra Petra Heffeter Medical University Vienna Schmidt, Wolfgang M. Wolfgang M. Schmidt Medical University of Vienna Nowikovsky, Karin Karin Nowikovsky 0000-0001-8435-8410 University of Veterinary Medicine Vienna Raynal, Noël J-M Noël J-M Raynal Université de Montréal Sgarioto, Nicolas Nicolas Sgarioto Université de Montréal Schaier, Martin Martin Schaier University of Vienna Regner, Benedict Benedict Regner Medical University Vienna Rusz, Mate Mate Rusz Medical University Vienna / University of Vienna Mohr, Thomas Thomas Mohr Medical University Vienna / University of Vienna Pirker, Christine Christine Pirker Medical University Vienna Schoenhacker-Alte, Beatrix Beatrix Schoenhacker-Alte Medical University Vienna / University of Vienna Mendrina, Theresa Theresa Mendrina Medical University Vienna / University of Vienna Wiley text eng The leading first-in-class ruthenium-complex BOLD-100 currently undergoes clinical phase-II anticancer evaluation. Recently, BOLD-100 is identified as anti-Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD-100-resistant colon and pancreatic carcinoma cells. Acute BOLD-100 treatment reduces lipid droplet contents of BOLD-100-sensitive but not -resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD-100-resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame-shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl-coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell-free BOLD-100-CoA adduct formation suggesting acetyl-CoA depletion as mechanism bridging BOLD-100-induced lipid metabolism alterations and histone acetylation-mediated gene expression deregulation. Indeed, BOLD-100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de-acetylation as central mode-of-action of BOLD-100 and metabolic programs stabilizing histone acetylation as relevant Achilles' heel of acquired BOLD-100-resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD-100 responsiveness. Summarizing, BOLD-100 is identified as epigenetically active substance acting via targeting several onco-metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD-100 resistance opens novel strategies to tackle therapy failure. Fatty-Acid Synthase; Endoplasmic-Reticulum Stress; Regulated Protein 78; Cancer-Cells; Plasma-Membrane; Expression; Drug; Inhibition; Coa; Er http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:2513/download 10.1002/advs.202301939 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Advanced Science 10(32) (2023) Advanced Science 10 32 5.27 MB 2023