Titel (eng)

The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation

Autor*in

Dina Baier   Medical University Vienna / University of Vienna

Walter Berger   Medical University Vienna

Bernhard K. Keppler   University of Vienna

Gunda Koellensperger   University of Vienna

Samuel M. Meier-Menches   University of Vienna / Medical University of Vienna

Petra Heffeter   Medical University Vienna

Wolfgang M. Schmidt   Medical University of Vienna

Karin Nowikovsky   University of Veterinary Medicine Vienna

Noël J-M Raynal   Université de Montréal

Nicolas Sgarioto   Université de Montréal

Martin Schaier   University of Vienna

Benedict Regner   Medical University Vienna

Mate Rusz   Medical University Vienna / University of Vienna

Thomas Mohr   Medical University Vienna / University of Vienna

Christine Pirker   Medical University Vienna

Beatrix Schoenhacker-Alte   Medical University Vienna / University of Vienna

Theresa Mendrina   Medical University Vienna / University of Vienna

Verlag

Wiley

Beschreibung (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.

Sprache des Objekts

Englisch

Datum

2023

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Fatty-Acid Synthase; Endoplasmic-Reticulum Stress; Regulated Protein 78; Cancer-Cells; Plasma-Membrane; Expression; Drug; Inhibition; Coa; Er

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