V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.
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Authors
Bartel, KarinWinzi, Maria
Ulrich, Melanie
Koeberle, Andreas
Menche, Dirk
Werz, Oliver
Müller, Rolf

Guck, Jochen
Vollmar, Angelika M
von Schwarzenberg, Karin
Issue Date
2017-02-07
Metadata
Show full item recordAbstract
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.Citation
V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy. 2017, 8 (6):9476-9487 OncotargetAffiliation
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.Journal
OncotargetPubMed ID
28036299Type
ArticleLanguage
enISSN
1949-2553ae974a485f413a2113503eed53cd6c53
10.18632/oncotarget.14339
Scopus Count
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
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