title: V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.
abstract: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide and the third leading cause of cancer-related death. However, therapy options are limited leaving an urgent need to develop new strategies. Currently, targeting cancer cell lipid and cholesterol metabolism is gaining interest especially regarding HCC. High cholesterol levels support proliferation, membrane-related mitogenic signaling and increase cell softness, leading to tumor progression, malignancy and invasive potential. However, effective ways to target cholesterol metabolism for cancer therapy are still missing. The V-ATPase inhibitor archazolid was recently shown to interfere with cholesterol metabolism. In our study, we report a novel therapeutic potential of V-ATPase inhibition in HCC by altering the mechanical phenotype of cancer cells leading to reduced proliferative signaling. Archazolid causes cellular depletion of free cholesterol leading to an increase in cell stiffness and membrane polarity of cancer cells, while hepatocytes remain unaffected. The altered membrane composition decreases membrane fluidity and leads to an inhibition of membrane-related Ras signaling resulting decreased proliferation in vitro and in vivo. V-ATPase inhibition represents a novel link between cell biophysical properties and proliferative signaling selectively in malignant HCC cells, providing the basis for an attractive and innovative strategy against HCC.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Bartel
authors.affiliation: Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Winzi
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, 53121 Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Menche
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Guck
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: von Schwarzenberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D018942:Macrolides / Q000494:pharmacology*; D008560:Membrane Fluidity / Q000187:drug effects*; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; D013844:Thiazoles; C519727:archazolid A; D002784:Cholesterol; D025262:Vacuolar Proton-Translocating ATPases; D018631:ras Proteins
keywords: HCC; Ras; V-ATPase; cell stiffness; cholesterol