No more tumour cells in a bind
E-cadherin is expressed on the surface of epithelial cells in many organs including the lungs, digestive tract and testis. It is responsible for the integrity of the mucosal tissues that are the first line of defence against toxic molecules in the environment. When cadherins bind to form dimers, they 'swap' strands in their so-called adhesive domains. This involves the insertion of the conserved tryptophan into an acceptor pocket of the partner molecule forming the dimer, two similar molecules joined together. The EU-funded project DETACH (Destabilization of the epithelial tissue architecture by competition with E-cadherin homo-dimer formation: small molecule-induced disruption of the epithelium integrity and functions) investigated the molecular dynamics of this adhesion process. DETACH aimed at determining the X-ray crystallographic structures of E-cadherin and other cadherins in complex with environmental pollutants such as polycyclic aromatic hydrocarbons. These compounds show structural and chemical similarity to the tryptophan side-chain and may therefore bind into the acceptor pocket, thus possibly disrupting epithelial tissue integrity. Although no complex structures could be obtained to prove such mechanism, the high resolution crystal structure of native P-cadherin was determined in the process. P-cadherin is a classical cadherin family member that had never been structurally characterized before and that is known to be involved is several diseases including cancer. Structure of E-cadherin binding with heavy metals was also investigated. Cadherins are calcium-dependent molecules. If this metal is replaced with a heavy metal pollutant – for example, mercury (Hg2+) or copper (Cu2+), the integrity of the epithelium will be disrupted. Scientists were unable to determine the crystal structure of the metal-substituted cadherins. However, the results suggest that heavy metal substitution is detrimental to function and impairs proper folding. DETACH also investigated a library of around 30 small molecules (peptidomimetics) specially selected by the team to bind into the cadherin acceptor pocket and modulate its adhesion properties.. This is one of the first attempts to design small molecules that will target the strand dimer interfaces identified by crystal structure analysis. Two of the selected compounds successfully inhibited E-cadherin adhesion, even at concentrations in the micromolar range. One of these peptides was successfully co-crystallized with E-cadherin. This result clearly provides new avenues for a structure-based drug design approach to the development of cadherin inhibitors as potential anti-cancer drugs. The compounds developed by DETACH could be used to investigate cell processes and develop new modulators of cell adhesion. Applications include innovative diagnostic and therapeutic strategies against certain cancers.
Keywords
Tumour, cell to cell adhesion, E-cadherin, adhesion inhibitors, heavy metals, antagonist
