RETINOID-X RECEPTOR-SPECIFIC RETINOIDS INHIBIT THE ABILITY OF RETINOIC ACID RECEPTOR-SPECIFIC RETINOIDS TO INCREASE THE LEVEL OF INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-3 IN HUMAN ECTOCERVICAL EPITHELIAL-CELLS

The hormones derived from vitamin A and related synthetic ligands (ret inoids) are important regulators of differentiation and development an d have been shown to be therapeutically useful in the treatment of cer vical cancer, All-trans-retinoic acid exerts its effects by activation of retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterod imers, These heterodimers bind to the retinoic acid response elements of target genes to regulate gene expression. RXR ligands act through R XR homodimers to regulate gene expression, In the present study, we de scribe the effects of RAR- and RXR-specific ligands on the regulation of insulinlike growth factor binding protein-3 (IGFBP-3) production an d cell proliferation in human ectocervical epithelial (ECE) cell lines , Treatment of ECE16-1 cells with a RAR-specific ligand (TTNPB) or a l igand that interacts with both RAR and RXR receptors (9-cis-retinoic a cid) increases IGFBP-3 levels and suppresses cell proliferation. In co ntrast, RXR-specific ligands (AGN191701, SR11217, and SR11237) do not regulate proliferation and slightly suppress the IGFBP-3 level, Cotrea tment with increasing concentrations (0.01-1000 nm) of RXR-specific li gand antagonizes the growth suppressive and IGFBP-3-increasing effects of 1000 nbr TTNPB, Similar results are observed in two other ECE cell lines, ECE16-D1 and ECE16-D2, These results indicate that RXR-specifi c ligands can antagonize RAR responses in these cell lines and suggest that a RAR-specific retinoid may be superior to one with mixed RAR/RX R binding activity for inhibiting cervical cancer cell proliferation, Moreover, the antagonism of RAR-dependent responses by RXR-specific li gands is consistent with a squelching model in which the RXR-specific ligand drives formation of RXR/RXR homodimers at the expense of the mo re active RAR/RXR heterodimers.