title: Retinoic acid receptor β enhanced the anti-cancer stem cells effect of β-carotene by down-regulating expression of delta-like 1 homologue in human neuroblastoma cells.
abstract: Neuroblastoma (NB) is childhood malignancy that retains characteristics of cancer stem cells (CSCs). Targeting the CSCs is one of the therapeutic strategies proposed to achieve complete remission of NB. β-carotene (BC), an active precursor of retinoids, is a well-known antioxidant reported to possess anti-CSCs effects. Here, we investigated the involvement of retinoic acid receptors (RARs) in the anti-CSCs effects of BC. Treatment with BC or retinoic acid (RA) upregulated RARβ mRNA expression in two NB cell lines. Inhibition of RARβ using siRNA up-regulated gene expression of delta-like 1 homologue (DLK1), a marker of CSCs. To understand the molecular mechanisms of RARβ-mediated inhibition of DLK1, four retinoic acid receptor elements (RAREs) were identified in the promoter of DLK1. Chromatin immunoprecipitation assays indicated that RARβ bound directly to a RARE in the DLK1 promoter region. Knock-down of RARβ also increased the self-renewal capacity of NB cells, which was suppressed by BC. Taken together, this study provided evidence that the therapeutic anti-CSC effects of BC depend on RARβ and its ability to interact with and down-regulate the CSCs marker, DLK1.
authors.affiliation: Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, South Korea.
authors.forename: Yoo-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, South Korea.
authors.forename: Eunju
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, South Korea.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, South Korea. Electronic address: yuri.kim@ewha.ac.kr.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D019207:beta Carotene / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D019207:beta Carotene
keywords: Cancer stem cells; DLK1; Neuroblastoma; Retinoic acid β; β-carotene