All‐trans‐retinoic Acid‐dependent Inhibition of E‐Cadherin‐based Cell Adhesion with Concomitant Dephosphorylation of β‐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, 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.

Hormone‐activated nuclear receptors inhibit the stimulation of the JNK and ERK signalling pathways in endothelial cells

“…1 ). These two cell types were chosen as controls in view of the previously described hormone interference with AP‐1 activation [31]. In contrast, VDR RNA expression was only relevant in HMEC‐1 cells while it was undetectable in EOMA and MS‐1 lines.…”

“…The tissue‐ and urokinase‐type plasminogen activator proteases are regulated by RA [9,23–25]. Glucocorticoids, RA, and vitD3 also regulate the expression of several adhesion molecules that may contribute to the angiogenic process: intracellular adhesion molecule‐1 [26], vascular cellular adhesion molecule‐1 [27], E‐selectin [28], L‐selectin [29], tenascin [30], and E‐cadherin [31]. In most cases expression of these molecules is repressed by hormone‐bound nuclear receptors.…”

Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma

“…The inverse correlation between ALDH1A2 and vimentin expression in tumor cells was further supported in a mouse xenograft model in vivo and tumor sections from OPSCC patients. Although, the underlying molecular mechanism remains to be elucidated, several studies reported that ATRA inhibits tumor cell invasion and metastatic potential in diverse model systems by modulating cell-to-cell adhesion and RAR-dependent regulation of proteins implicated in epithelial-to-mesenchymal transition [ 22 – 25 ]. It is also worth noting that a continuous cultivation of FaDu cells in the presence of WIN18.446 or BMS493, respectively, results in formation of stable and expandable tumorspheres, suggesting that tumor cells lacking ALDH1A2-RAR signaling also gain the capacity to avoid anoikis and acquire stem cell traits (unpublished data).…”

Retinoic acid is a negative physiological regulator of N‐cadherin during early avian heart morphogenesis

“…While there is evidence that RA alters the cadherin‐catenin pathways in cell culture (Jonk et al. 1994; Ryuto et al. 1997; Shah et al.…”