9-cis retinoic acid induces insulin-like growth factor binding protein-3 through DR-8 retinoic acid responsive elements.

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Chang YS, Cho JY, Cho HA, Kim HJ, Chang J, Ahn CM, Kim SK, Kim SK

9-cis retinoic acid induces insulin-like growth factor binding protein-3 through DR-8 retinoic acid responsive elements.

Cancer Biol Ther. 2006 Jun;5(6):586-92. Epub 2006 Jun 5.

PubMed ID

16760641 [ View in PubMed

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Abstract

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-beta (RAR-beta). 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 induced IGFBP-3 expression in dose- and time-dependent manners. Transient transfection with a reporter constructs 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 cotransfection assay with a RAR-beta expression vector potentiated (and with siRNA for RAR-beta, 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-beta, a putative tumor suppressor in NSCLC.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Alitretinoin	Insulin-like growth factor-binding protein 3	Protein	Humans	Unknown	Not Available	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Alitretinoin	Approved Investigational	IGFBP3	3486	upregulated	alitretinoin results in increased expression of IGFBP3 mRNA	7p12.3