Baier, Dina (Medical University Vienna / University of Vienna) Dina Baier Berger, Walter (Medical University Vienna) Walter Berger Schaier, Martin (University of Vienna) Martin Schaier Regner, Benedict (Medical University Vienna) Benedict Regner Rusz, Mate (Medical University Vienna / University of Vienna) Mate Rusz Mohr, Thomas (Medical University Vienna / University of Vienna) Thomas Mohr Pirker, Christine (Medical University Vienna) Christine Pirker Schoenhacker-Alte, Beatrix (Medical University Vienna / University of Vienna) Beatrix Schoenhacker-Alte Mendrina, Theresa (Medical University Vienna / University of Vienna) Theresa Mendrina Keppler, Bernhard K. (University of Vienna) Bernhard K. Keppler Koellensperger, Gunda (University of Vienna) Gunda Koellensperger Meier-Menches, Samuel M. (University of Vienna / Medical University of Vienna) Samuel M. Meier-Menches Heffeter, Petra (Medical University Vienna) Petra Heffeter Schmidt, Wolfgang M. (Medical University of Vienna) Wolfgang M. Schmidt Nowikovsky, Karin (University of Veterinary Medicine Vienna) Karin Nowikovsky Raynal, Noël J-M (Université de Montréal) Noël J-M Raynal Sgarioto, Nicolas (Université de Montréal) Nicolas Sgarioto Wiley 2023 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. PDFDocument en 2024-02-13T08:37:53.016Z Fatty-Acid Synthase; Endoplasmic-Reticulum Stress; Regulated Protein 78; Cancer-Cells; Plasma-Membrane; Expression; Drug; Inhibition; Coa; Er 5521168 b application/pdf CC BY 4.0 International