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Research Paper

9-cis Retinoic Acid Induces Insulin-like Growth Factor Binding Protein-3 Through DR-8 Retinoic Acid Responsive Elements

Yoon Soo Chang, Jae Yong Cho, Hyun A Cho, Hyung Jung Kim, Joon Chang, Chul Min Ahn, Sung Kyu Kim and Se Kyu Kim

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Retinoic acids, which have shown potential chemopreventive and therapeutic activities for several neoplastic diseases in vitro, modulate the growth-promoting and anti-apoptotic activities of insulin-like growth factors (IGFs), in part by influencing the expression of insulin-like growth factor binding protein-3 (IGFBP-3). This study sought to investigate the effect of 9-cis retinoic acid (9cRA) on the expression of IGFBP-3 and the underlying mechanisms involving retinoic acid receptor-β (RAR-ββ).The pharmacologic activity of 9cRA was characterized by monitoring target modulation as well as by evaluating the underlying mechanisms in NSCLC cells. Treatment of 9cRA inhibited proliferation of a part of NSCLC cell lines including H460 cells in clinically-achievable concentrations and induce IGFBP-3 expression in dose- and time-dependent manners. Transient transfection with a reporter construct driven by the human IGFBP-3 gene promoter indicated that 9cRA induces gene expression via the -534 to -445 region (relative to translation start site) of the IGFBP-3 promoter. Unilateral deletion and site-directed mutagenesis identified a retinoic acid responsive element (RARE), a direct repeat of two GGGTCA-related hexanucleotides separated by just 8 bp (DR-8-type response element). A co-transfection assay with a RAR-β expression vector potentiated (and with siRNA for RAR-β, diminished) the effect of 9cRA on IGFBP-3 expression. IGFBP-3 gene expression by 9cRA is mediated by a distinct DR-8 RARE located in the proximal region of the IGFBP promoter and involves the RAR-β, a putative tumor suppressor in NSCLC.

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.