Wiley 2023 isPartOf:https://phaidra.vetmeduni.ac.at/o:605 The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation Baier, Dina (Medical University Vienna / University of Vienna) Berger, Walter (Medical University Vienna) Schaier, Martin (University of Vienna) Regner, Benedict (Medical University Vienna) Rusz, Mate (Medical University Vienna / University of Vienna) Mohr, Thomas (Medical University Vienna / University of Vienna) Pirker, Christine (Medical University Vienna) Schoenhacker-Alte, Beatrix (Medical University Vienna / University of Vienna) Mendrina, Theresa (Medical University Vienna / University of Vienna) Keppler, Bernhard K. (University of Vienna) Koellensperger, Gunda (University of Vienna) Meier-Menches, Samuel M. (University of Vienna / Medical University of Vienna) Heffeter, Petra (Medical University Vienna) Schmidt, Wolfgang M. (Medical University of Vienna) Nowikovsky, Karin (University of Veterinary Medicine Vienna) Raynal, Noël J-M (Université de Montréal) Sgarioto, Nicolas (Université de Montréal) 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. doi:10.1002/advs.202301939 https://phaidra.vetmeduni.ac.at/o:2513 CC BY 4.0 International http://creativecommons.org/licenses/by/4.0/ eng Fatty-Acid Synthase; Endoplasmic-Reticulum Stress; Regulated Protein 78; Cancer-Cells; Plasma-Membrane; Expression; Drug; Inhibition; Coa; Er Advanced Science 10(32) (2023) application/pdf article