All‐trans‐retinoic Acid‐dependent Inhibition of E‐Cadherin‐based Cell Adhesion with Concomitant Dephosphorylation of β‐Catenin in Metastatic Human Renal Carcinoma Cells

We previously described an in vitro invasion assay model, using a monolayer of vascular endothelial cells grown on collagen gel, that mimics the metastatic abilities of the highly metastatic human renal carcinoma cell lines, MM‐1,3 and 8 and their poorly metastatic counterparts, SN12C and Q‐8. MM‐1, 3 and 8 cells were observed to penetrate the monolayer of vascular endothelial cells and grew in a spreading or scattering manner with loose cell‐cell contact on collagen gel or on vascular endothelial cells. SN12C and Cl‐8 cells failed to penetrate and grew in a clustering manner with tight cell‐cell contact. Treatment with all‐ trans ‐retinoic acid (ATRA) at non‐toxic concentrations induced clustering or growth of MM‐1, 3 and 8 cells on collagen gel or on vascular endothelial cells with tight cell‐cell contact, and inhibited penetration. The clustering induced by ATRA was virtually blocked in the presence of anti‐E cadherin antibody. E‐Cadherin and β ‐catenin were each localized mainly at the cell‐cell adherent junctions of colonizing cell populations that had been treated with ATRA. While the cellular levels of E‐cadherin and β ‐catenin did not change significantly following ATRA treatment, the tyrosine residue of β ‐catenin was rapidly dephosphorylated. The concomitant administration of Na vanadate, an inhibitor of tyrosine dephosphorylase, inhibited both the ATRA‐induced clustering and the dephosphorylation of β ‐catenin tyrosine. ATRA‐induced clustering of MM‐3 cells may be linked to the state of tyrosine phosphorylation of β ‐catenin.