title: Vacuolar-ATPase Inhibition Blocks Iron Metabolism to Mediate Therapeutic Effects in Breast Cancer.
abstract: Generalized strategies to improve breast cancer treatment remain of interest to develop. In this study, we offer preclinical evidence of an important metabolic mechanism underlying the antitumor activity of inhibitors of the vacuolar-type ATPase (V-ATPase), a heteromultimeric proton pump. Specifically, our investigations in the 4T1 model of metastatic breast cancer of the V-ATPase inhibitor archazolid suggested that its ability to trigger metabolic stress and apoptosis associated with tumor growth inhibition related to an interference with hypoxia-inducible factor-1α signaling pathways and iron metabolism. As a consequence of disturbed iron metabolism, archazolid caused S-phase arrest, double-stranded DNA breaks, and p53 stabilization, leading to apoptosis. Our findings link V-ATPase to cell-cycle progression and DNA synthesis in cancer cells, and highlight the basis for the clinical exploration of V-ATPase as a potentially generalizable therapy for breast cancer.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Lina S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: von Schwarzenberg
authors.affiliation: Clinical Pharmacy, Saarland University, Saarbrücken, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Kubisch-Dohmen
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Liebl
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
authors.affiliation: Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Menche
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Munich, Germany. angelika.vollmar@cup.uni-muenchen.de.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism*; D061986:MCF-7 Cells; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; D013844:Thiazoles; C519727:archazolid A; D007501:Iron; D025262:Vacuolar Proton-Translocating ATPases