o:2513 The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation en 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 1552099 10.1002/advs.202301939 2024-02-13T08:37:53.016Z 44 yes 46 Dina Baier Medical University Vienna / University of Vienna Theresa Mendrina Medical University Vienna / University of Vienna person Beatrix Schoenhacker-Alte Medical University Vienna / University of Vienna person Christine Pirker Medical University Vienna person Thomas Mohr Medical University Vienna / University of Vienna person Mate Rusz Medical University Vienna / University of Vienna person Benedict Regner Medical University Vienna person Martin Schaier University of Vienna person Nicolas Sgarioto Université de Montréal person Noël J-M Raynal Université de Montréal person Karin Nowikovsky University of Veterinary Medicine Vienna person 0000-0001-8435-8410 Wolfgang M. Schmidt Medical University of Vienna person Petra Heffeter Medical University Vienna person Samuel M. Meier-Menches University of Vienna / Medical University of Vienna person Gunda Koellensperger University of Vienna person Bernhard K. Keppler University of Vienna person Walter Berger Medical University Vienna person 0000-0003-0014-1658 application/pdf 5521168 https://phaidra.vetmeduni.ac.at/o:2513 no yes 16 70 1552253 Advanced Science 19 10 32 Wiley 2023