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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 Cells¹

Departments of Physiology and Biophysics [J. R. H., C. A., R. L. E.], Dermatology [R. L. E.], Reproductive Biology [R. L. E.], and Biochemistry [R. L. E.], Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, and Retinoid Research, Departments of Chemistry [R. L. B., R. A. S. C.] and Biology [R. A. S. C], Allergan Incorporated, Irvine, California 92713

The hormones derived from vitamin A and related synthetic ligands (retinoids) are important regulators of differentiation and development and have been shown to be therapeutically useful in the treatment of cervical cancer. All-trans-retinoic acid exerts its effects by activation of retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterodimers. These heterodimers bind to the retinoic acid response elements of target genes to regulate gene expression. RXR ligands act through RXR homodimers to regulate gene expression. In the present study, we describe the effects of RAR- and RXR-specific ligands on the regulation of insulin-like growth factor binding protein-3 (IGFBP-3) production and cell proliferation in human ectocervical epithelial (ECE) cell lines. Treatment of ECE16-1 cells with a RAR-specific ligand (TTNPB) or a ligand that interacts with both RAR and RXR receptors (9-cis-retinoic acid) increases IGFBP-3 levels and suppresses cell proliferation. In contrast, RXR-specific ligands (AGN191701, SR11217, and SR11237) do not regulate proliferation and slightly suppress the IGFBP-3 level. Cotreatment with increasing concentrations (0.01–1000 nm) of RXR-specific ligand antagonizes the growth suppressive and IGFBP-3-increasing effects of 1000 nM TTNPB. Similar results are observed in two other ECE cell lines, ECE16-D1 and ECE16-D2. These results indicate that RXR-specific ligands can antagonize RAR responses in these cell lines and suggest that a RAR-specific retinoid may be superior to one with mixed RAR/RXR binding activity for inhibiting cervical cancer cell proliferation. Moreover, the antagonism of RAR-dependent responses by RXR-specific ligands is consistent with a squelching model in which the RXR-specific ligand drives formation of RXR/RXR homodimers at the expense of the more active RAR/RXR heterodimers.

¹ This work was supported by a grant from Allergan Incorporated (to R. L. E.). The American Institute for Cancer Research (to R. L. E.) supported the development of the ECE16-1, ECE16-D1, and ECE16-D2 cell lines, which utilized the facilities of the Skin Diseases Research Center of Northeast Ohio (NIH Grant AR39750). J. R. H. was supported as a postdoctoral trainee in the Metabolism Training Program (NIH Grant DK07319).

² To whom requests for reprints should be addressed, at Department of Physiology/Biophysics, Room E532, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH 44106-4970. Phone: (216) 368-5530; Fax: (216) 368-5586.

Received 11/ 2/95. Accepted 2/16/96.

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