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1.
001-es BibID:
BIBFORM050058
Első szerző:
Schwarzenberg, Karin von
Cím:
V-ATPase inhibition overcomes trastuzumab resistance in breast cancer / Karin von Schwarzenberg, Tamás Lajtos, László Simon, Rolf Müller, György Vereb, Angelika M. Vollmar
Dátum:
2014
Megjegyzések:
The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H(+)-ATPase (V-ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V-ATPase opens a new therapeutic strategy against trastuzumab-resistant tumor cells in vitro and in vivo. V-ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro-survival signaling of the trastuzumab-resistant cell line JIMT-1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT-1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2-recycling which leads to reduced tumor growth. These results suggest that V-ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab-resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2-signaling in vitro as well as in vivo. V-ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab-resistant tumors
Tárgyszavak:
Orvostudományok
Elméleti orvostudományok
idegen nyelvű folyóiratközlemény külföldi lapban
analysis
Apoptosis
article
Biophysics
cell biology
Cell Line
Cells
Cytosol
Endosomes
EXPRESSION
GROWTH
Hungary
In Vitro
Mice
Research
Trastuzumab resistance
TUMORS
Megjelenés:
Molecular Oncology. - 8 : 1 (2014), p. 9-19. -
További szerzők:
Lajtos Tamás
Simon László (biofizikus)
Müller, Rolf
Vereb György (1965-) (biofizikus, orvos)
Vollmar, Angelika M.
Internet cím:
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon:
2.
001-es BibID:
BIBFORM044944
Első szerző:
Wiedmann, Romina M.
Cím:
The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1 / Romina M. Wiedmann, Karin von Schwarzenberg, Andrea Palamidessi, Laura Schreiner, Rebekka Kubisch, Johanna Liebl, Christina Schempp, Dirk Trauner, Gyorgy Vereb, Stefan Zahler, Ernst Wagner, Rolf Müller, Giorgio Scita, Angelika M. Vollmar
Dátum:
2012
Megjegyzések:
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
Tárgyszavak:
Orvostudományok
Elméleti orvostudományok
idegen nyelvű folyóiratközlemény külföldi lapban
ACTIVATION
article
Cells
EGFR
Epidermal Growth Factor
EPIDERMAL-GROWTH-FACTOR
GROWTH
In Vitro
Metastasis
mouse
Movement
Research
Research Support
Support
TUMORS
Megjelenés:
Cancer Research. - 72 : 22 (2012), p. 5976-5987. -
További szerzők:
Schwarzenberg, Karin von
Palamidessi, Andrea
Schreiner, Laura
Kubisch, Rebekka
Liebl, Johanna
Schempp, Christina
Trauner, Dirk
Vereb György (1965-) (biofizikus, orvos)
Zahler, Stefan
Wagner, Ernst
Müller, Rolf
Scita, Giorgio
Vollmar, Angelika M.
Internet cím:
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon:
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