Deletion of exon 8 increases cisplatin-induced E-cadherin cleavage

Exp Cell Res. 2008 Jan 1;314(1):153-63. doi: 10.1016/j.yexcr.2007.09.004. Epub 2007 Sep 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / pathology
  • Adherens Junctions / genetics
  • Adherens Junctions / metabolism
  • Adherens Junctions / pathology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Cadherins / drug effects
  • Cadherins / genetics*
  • Cadherins / metabolism*
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Drug Resistance, Neoplasm / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Exons / genetics
  • Female
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Mutation / genetics
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Invasiveness / physiopathology
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / physiopathology
  • Signal Transduction / physiology
  • beta Catenin / metabolism


  • Antineoplastic Agents
  • Cadherins
  • beta Catenin
  • Cisplatin