The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1.

2.50
Hdl Handle:
http://hdl.handle.net/10033/266912
Title:
The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1.
Authors:
Wiedmann, Romina M; von Schwarzenberg, Karin; Palamidessi, Andrea; Schreiner, Laura; Kubisch, Rebekka; Liebl, Johanna; Schempp, Christina; Trauner, Dirk; Vereb, Gyorgy; Zahler, Stefan; Wagner, Ernst; Müller, Rolf; Scita, Giorgio; Vollmar, Angelika M
Abstract:
The abundance of the multimeric vacuolar ATP-dependent proton pump, V-ATPase, on the plasma membrane of tumor cells correlates with the invasiveness of the tumor cell, suggesting the involvement of V-ATPase in tumor metastasis. V-ATPase is hypothesized to create a proton efflux leading to an acidic pericellular microenvironment that promotes the activity of proinvasive proteases. An alternative, not yet explored possibility is that V-ATPase regulates the signaling machinery responsible for tumor cell migration. Here, we show that pharmacologic or genetic reduction of V-ATPase activity significantly reduces migration of invasive tumor cells in vitro. Importantly, the V-ATPase inhibitor archazolid abrogates tumor dissemination in a syngeneic mouse 4T1 breast tumor metastasis model. Pretreatment of cancer cells with archazolid impairs directional motility by preventing spatially restricted, leading edge localization of epidermal growth factor receptor (EGFR) as well as of phosphorylated Akt. Archazolid treatment or silencing of V-ATPase inhibited Rac1 activation, as well as Rac1-dependent dorsal and peripheral ruffles by inhibiting Rab5-mediated endocytotic/exocytotic trafficking of Rac1. The results indicate that archazolid effectively decreases metastatic dissemination of breast tumors by impairing the trafficking and spatially restricted activation of EGFR and Rho-GTPase Rac1, which are pivotal for directed movement of cells. Thus, our data reveals a novel mechanism underlying the role of V-ATPase in tumor dissemination.
Affiliation:
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Citation:
The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1. 2012, 72 (22):5976-87 Cancer Res.
Journal:
Cancer research
Issue Date:
15-Nov-2012
URI:
http://hdl.handle.net/10033/266912
DOI:
10.1158/0008-5472.CAN-12-1772
PubMed ID:
22986742
Type:
Article
Language:
en
ISSN:
1538-7445
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorWiedmann, Romina Men_GB
dc.contributor.authorvon Schwarzenberg, Karinen_GB
dc.contributor.authorPalamidessi, Andreaen_GB
dc.contributor.authorSchreiner, Lauraen_GB
dc.contributor.authorKubisch, Rebekkaen_GB
dc.contributor.authorLiebl, Johannaen_GB
dc.contributor.authorSchempp, Christinaen_GB
dc.contributor.authorTrauner, Dirken_GB
dc.contributor.authorVereb, Gyorgyen_GB
dc.contributor.authorZahler, Stefanen_GB
dc.contributor.authorWagner, Ernsten_GB
dc.contributor.authorMüller, Rolfen_GB
dc.contributor.authorScita, Giorgioen_GB
dc.contributor.authorVollmar, Angelika Men_GB
dc.date.accessioned2013-01-24T15:23:39Z-
dc.date.available2013-01-24T15:23:39Z-
dc.date.issued2012-11-15-
dc.identifier.citationThe V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1. 2012, 72 (22):5976-87 Cancer Res.en_GB
dc.identifier.issn1538-7445-
dc.identifier.pmid22986742-
dc.identifier.doi10.1158/0008-5472.CAN-12-1772-
dc.identifier.urihttp://hdl.handle.net/10033/266912-
dc.description.abstractThe abundance of the multimeric vacuolar ATP-dependent proton pump, V-ATPase, on the plasma membrane of tumor cells correlates with the invasiveness of the tumor cell, suggesting the involvement of V-ATPase in tumor metastasis. V-ATPase is hypothesized to create a proton efflux leading to an acidic pericellular microenvironment that promotes the activity of proinvasive proteases. An alternative, not yet explored possibility is that V-ATPase regulates the signaling machinery responsible for tumor cell migration. Here, we show that pharmacologic or genetic reduction of V-ATPase activity significantly reduces migration of invasive tumor cells in vitro. Importantly, the V-ATPase inhibitor archazolid abrogates tumor dissemination in a syngeneic mouse 4T1 breast tumor metastasis model. Pretreatment of cancer cells with archazolid impairs directional motility by preventing spatially restricted, leading edge localization of epidermal growth factor receptor (EGFR) as well as of phosphorylated Akt. Archazolid treatment or silencing of V-ATPase inhibited Rac1 activation, as well as Rac1-dependent dorsal and peripheral ruffles by inhibiting Rab5-mediated endocytotic/exocytotic trafficking of Rac1. The results indicate that archazolid effectively decreases metastatic dissemination of breast tumors by impairing the trafficking and spatially restricted activation of EGFR and Rho-GTPase Rac1, which are pivotal for directed movement of cells. Thus, our data reveals a novel mechanism underlying the role of V-ATPase in tumor dissemination.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Cancer researchen_GB
dc.titleThe V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.en_GB
dc.identifier.journalCancer researchen_GB

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