V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy
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Karin Bartel1, Maria Winzi2, Melanie Ulrich1, Andreas Koeberle3, Dirk Menche4, Oliver Werz3, Rolf Müller5, Jochen Guck2, Angelika M. Vollmar1, Karin von Schwarzenberg1
1Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
2Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany
3Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany
4Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, 53121 Bonn, Germany
5Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Saarland University, 66123 Saarbrücken, Germany
Karin von Schwarzenberg, email: [email protected]
Keywords: HCC, cholesterol, V-ATPase, cell stiffness, Ras
Received: August 08, 2016 Accepted: December 12, 2016 Published: December 28, 2016
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.
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