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Deletion of exon 8 increases cisplatin-induced E-cadherin cleavage.
Exp. Cell Res. 314, 153-163 (2008)
E-Cadherin-mediated cell-cell adhesion plays a key role in epithelial cell survival and loss of E-cadherin or beta-catenin expression is associated with invasive tumor growth. Somatic E-cadherin mutations have been identified in sporadic diffuse-type gastric carcinoma. Here, we analysed the fate of E-cadherin with an in frame deletion of exon 8 compared to wild-type E-cadherin and the involved signalling events during cisplatin-induced apoptosis. We report that mutant E-cadherin was more readily cleaved during apoptosis than the wild-type form. Also beta-catenin, an important binding partner of E-cadherin, was processed. E-cadherin cleavage resulted in disconnection of the actin cytoskeleton and accumulation of E-cadherin and beta-catenin in the cytoplasm. Inhibitor studies demonstrated that E-cadherin cleavage was caused by a caspase-3-mediated mechanism. We identified the Akt/PKB and the ERK1/2 signalling pathways as important regulators since inhibition resulted in increased E-cadherin cleavage and apoptosis. In summary, we clearly demonstrate that somatic E-cadherin mutations affect apoptosis regulation in that way that they can facilitate the disruption of adherens junctions thereby possibly influencing the response to cisplatin-based chemotherapy. Elucidating the mechanisms that regulate the apoptotic program of tumor cells can contribute to a better understanding of tumor development and potentially be relevant for therapeutic drug design.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter E-cadherin; Cleavage; Cisplatin; Akt/protein kinase B; E-cadherin mutations
ISSN (print) / ISBN 1090-2422
Zeitschrift Experimental Cell Research
Quellenangaben Band: 314, Heft: 1, Seiten: 153-163
Verlag Academic Press
Verlagsort Orlando, Fla.
Begutachtungsstatus Peer reviewed