All-trans-retinoic acid-dependent inhibition of E-cadherin-based cell adhesion with concomitant dephosphorylation of beta-catenin in metastatic human renal carcinoma cells

Jpn J Cancer Res. 1997 Oct;88(10):982-91. doi: 10.1111/j.1349-7006.1997.tb00319.x.


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 Cl-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 beta-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 beta-catenin did not change significantly following ATRA treatment, the tyrosine residue of beta-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 beta-catenin tyrosine. ATRA-induced clustering of MM-3 cells may be linked to the state of tyrosine phosphorylation of beta-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cadherins / immunology
  • Cadherins / metabolism*
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / secondary
  • Cattle
  • Cell Adhesion* / drug effects
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism*
  • Endothelium, Vascular / metabolism
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Male
  • Mice
  • Microscopy, Confocal
  • Phosphorylation / drug effects
  • Trans-Activators*
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured
  • Vanadates / pharmacology
  • beta Catenin


  • Antineoplastic Agents
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cadherins
  • Cytoskeletal Proteins
  • Trans-Activators
  • beta Catenin
  • Vanadates
  • Tretinoin