V-ATPase inhibition overcomes trastuzumab resistance in breast cancer
| Autor: | Tamás Lajtos, László Simon, Angelika M. Vollmar, Rolf Müller, György Vereb, Karin von Schwarzenberg |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Vacuolar Proton-Translocating ATPases Endosome Receptor ErbB-2 ATPase Antineoplastic Agents Breast Neoplasms Mice SCID Biology Endocytosis Antibodies Monoclonal Humanized chemistry.chemical_compound Mice Cell Line Tumor Genetics V-ATPase Animals Humans Breast Enzyme Inhibitors skin and connective tissue diseases neoplasms Research Articles Oncogene General Medicine Trastuzumab Cell biology Gene Expression Regulation Neoplastic Oncology chemistry Cell culture Apoptosis Drug Resistance Neoplasm biology.protein Molecular Medicine Female Growth inhibition |
| Zdroj: | Molecular oncology. 8(1) |
| ISSN: | 1878-0261 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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