Differential regulation of a fibroblast growth factor-binding protein by receptor-selective analogs of retinoic acid

We have demonstrated earlier that a secreted fibroblast growth factor-binding protein (FGF-BP) can enhance angiogenesis and promote tumor growth in vivo. Furthermore, we found that FGF-BP expression in squamous cell carcinoma (SCC) is reduced by concentrations of retinoids that are effective in the treatment of SCC and that this repression can occur at the transcriptional and post-transcriptional level. To further examine the mechanism of regulation of FGF-BP by retinoids and the role played by retinoid receptor subtypes, we utilized retinoic acid receptor (RAR)-selective (TTNPB) and retinoid X receptor (RXR)-selective (LG100268) ligands. In ME-180 SCC cells, FGF-BP mRNA was down-regulated by TTNPB with an IC50 value of 1 nM, whereas transcription was only repressed at 10,000-fold higher concentrations (IC50 > 10 muM) This suggests that the major effects of retinoids on FGF-BP occur at the post-transcriptional level. In four additional SCC cell lines, FGF-BP was also down-regulated by TTNPB with IC50 values of less than or equal to 1 nM, demonstrating that RAR receptors can modulate FGF-BP mRNA levels very effectively in SCC cells. The IUCR-selective ligand on its own was only effective in two of the five cell lines (IC50 of approximate to 1 nM). In all of the SCC cell lines, a low concentration of RAR sensitized FGF-BP mRNA to treatment with the RXR ligand and the combination of the RXR and RAR ligands enhanced the efficacy beyond that of the individual ligands. We conclude that RAR receptors are major regulators of FGF-BP mRNA at the post-transcriptional level and propose that an RAR-induced gene product mediates the RXR effects on FGF-BP mRNA. (C) 2000 Elsevier Science Inc.