Deletion of exon 8 increases cisplatin-induced E-cadherin cleavage.
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.
Fuchs
Margit
M
Technische Universität München, Klinikum rechts der Isar, Institut für Allgemeine Pathologie und Pathologische Anatomie, D-81675 München, Germany.
Hermannstädter
Christine
C
Hutzler
Peter
P
Häcker
Georg
G
Haller
Ferdinand
F
Höfler
Heinz
H
Luber
Birgit
B
D008841:Actin Cytoskeleton / Q000473:pathology; D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015820:Cadherins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000503:physiopathology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
D000970:Antineoplastic Agents; D015820:Cadherins; D051176:beta Catenin; D002945:Cisplatin