V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621092
Title:
V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.
Authors:
Bartel, Karin; Winzi, Maria; Ulrich, Melanie; Koeberle, Andreas; Menche, Dirk; Werz, Oliver; Müller, Rolf ( 0000-0002-1042-5665 ) ; Guck, Jochen; Vollmar, Angelika M; von Schwarzenberg, Karin
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.
Affiliation:
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
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 Oncotarget
Journal:
Oncotarget
Issue Date:
7-Feb-2017
URI:
http://hdl.handle.net/10033/621092
DOI:
10.18632/oncotarget.14339
PubMed ID:
28036299
Type:
Article
Language:
en
ISSN:
1949-2553
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorBartel, Karinen
dc.contributor.authorWinzi, Mariaen
dc.contributor.authorUlrich, Melanieen
dc.contributor.authorKoeberle, Andreasen
dc.contributor.authorMenche, Dirken
dc.contributor.authorWerz, Oliveren
dc.contributor.authorMüller, Rolfen
dc.contributor.authorGuck, Jochenen
dc.contributor.authorVollmar, Angelika Men
dc.contributor.authorvon Schwarzenberg, Karinen
dc.date.accessioned2017-09-05T13:22:21Z-
dc.date.available2017-09-05T13:22:21Z-
dc.date.issued2017-02-07-
dc.identifier.citationV-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy. 2017, 8 (6):9476-9487 Oncotargeten
dc.identifier.issn1949-2553-
dc.identifier.pmid28036299-
dc.identifier.doi10.18632/oncotarget.14339-
dc.identifier.urihttp://hdl.handle.net/10033/621092-
dc.description.abstractHepatocellular 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleV-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.en
dc.typeArticleen
dc.contributor.departmentHIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalOncotargeten

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