phaidra.vetmeduni.ac.at o:2513 DOI 10.1002/advs.202301939 The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation 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. eng Fatty-Acid Synthase; Endoplasmic-Reticulum Stress; Regulated Protein 78; Cancer-Cells; Plasma-Membrane; Expression; Drug; Inhibition; Coa; Er 2024-02-13T08:52:20.376Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Baier;Dina; FN:Dina Baier END:VCARD BEGIN:VCARD VERSION:3.0 N:Berger;Walter; FN:Walter Berger X-ORCID:https://orcid.org/0000-0003-0014-1658 END:VCARD BEGIN:VCARD VERSION:3.0 N:Keppler;Bernhard K.; FN:Bernhard K. Keppler END:VCARD BEGIN:VCARD VERSION:3.0 N:Koellensperger;Gunda; FN:Gunda Koellensperger END:VCARD BEGIN:VCARD VERSION:3.0 N:Meier-Menches;Samuel M.; FN:Samuel M. Meier-Menches END:VCARD BEGIN:VCARD VERSION:3.0 N:Heffeter;Petra; FN:Petra Heffeter END:VCARD BEGIN:VCARD VERSION:3.0 N:Schmidt;Wolfgang M.; FN:Wolfgang M. Schmidt END:VCARD BEGIN:VCARD VERSION:3.0 N:Nowikovsky;Karin; FN:Karin Nowikovsky X-ORCID:https://orcid.org/0000-0001-8435-8410 END:VCARD BEGIN:VCARD VERSION:3.0 N:Raynal;Noël J-M; FN:Noël J-M Raynal END:VCARD BEGIN:VCARD VERSION:3.0 N:Sgarioto;Nicolas; FN:Nicolas Sgarioto END:VCARD BEGIN:VCARD VERSION:3.0 N:Schaier;Martin; FN:Martin Schaier END:VCARD BEGIN:VCARD VERSION:3.0 N:Regner;Benedict; FN:Benedict Regner END:VCARD BEGIN:VCARD VERSION:3.0 N:Rusz;Mate; FN:Mate Rusz END:VCARD BEGIN:VCARD VERSION:3.0 N:Mohr;Thomas; FN:Thomas Mohr END:VCARD BEGIN:VCARD VERSION:3.0 N:Pirker;Christine; FN:Christine Pirker END:VCARD BEGIN:VCARD VERSION:3.0 N:Schoenhacker-Alte;Beatrix; FN:Beatrix Schoenhacker-Alte END:VCARD BEGIN:VCARD VERSION:3.0 N:Mendrina;Theresa; FN:Theresa Mendrina END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 5521168 https://phaidra.vetmeduni.ac.at/o:2513 https://phaidra.vetmeduni.ac.at/api/object/o:2513/thumbnail LOMv1.0 discipline