All-trans-retinoic Acid-Dependent Inhibition of E-Cadherin-Based Cell Adhesion With Concomitant Dephosphorylation of beta-Catenin in Metastatic Human Renal Carcinoma Cells

Abstract

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, SNl2C and C1-8. MM-1, 3 and 8 cells were obsemed 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, SNl2C and C1-8 cells failed to penetrate, and grew in a clustering manner with tight cell-cell contact. Treatment with all-transretinoic 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 p-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 p-catenin did not change significantly following ATRA treatment, the tyrosine residue of &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 p-catenin tyrosine. ATRA-induced clustering of MM-3 cells may be linked to the state of tyrosine phosphorylation of p-catenin. Editorial Comment: Differentiating agents have been investigated and used in the treatment of cancer. These authors used an in vitro assay of a monolayer of vascular endothelial cells grown on collagen gel to evaluate the metastatic capabilities of human renal cell carcinoma cell lines. Retinoic acids may inhibit tumor cell invasion by suppressing type 4 collagenase but there was no good evidence for this process in this study. All-trans-retinoic acid produced a favorable morphological change in highly metastatic cells which was inhibited when an anti-E-cadherin was present. The Ecadherin pathway maybe involved with these metastatic cella Ecadherin interads with atenins, inchding pcatenh Phasphoryhtion of -tenin is known to abolish the cell adhesion of cancer cells. A deletion of -tenin also may disrupt the interaction with Ecadherin and result in loss of cellular adhesiveness. In smmmary, All-traxwretinoic acid inhibited the invasion of highly metr &tic human renal cell carcinoma cell line and induced marked clustering of these cells.