Retinoic acid (RA) receptor transcriptional activation correlates with inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase (ODC) activity by retinoids: A potential role for trans-RA-induced ZBP-89 in ODC inhibition

Evaluation of retinoic acid receptor (RAR) subtype-selective α and γ agonists and antagonists and a retinoid X receptor (RXR) class-selective agonist for efficacy at inhibiting both induction of ornithine decarboxylase (ODC) by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis and rat tracheal epithelial cells and the appearance of papillomas in mouse epidermis treated in the 2-stage tumor initiation-promotion model indicated that (i) RXR class-selective transcriptional agonists, such as MMII246, were not involved in ODC inhibition; (ii) RAR-selective agonists that induce gene transcription from RAresponsive elements (RAREs) were active at low concentrations; (iii) RAR-selective antagonists that bind RARs and inhibit AP-I activation on the collagenase promoter but do not activate RAREs to induce gene transcription were less effective inhibitors; and (iv) RARγ-selective retinoid agonists were more effective inhibitors of TPA-induced ODC activity than RARα-selective agonists. These results suggest that RARE activation has a more important role in inhibition of ODC activity than RXR activation or AP-I inhibition and that RARγ-selective agonists would be the most useful inhibitors of epithelial cell proliferation induced by tumor promoters. The natural retinoid all-trans-RA induced expression of transcription factor ZBP-89, which represses activation of the GC box in the ODC promoter by the transcription factor SpI. (C) 2001 WiIey-Liss, Inc.