Retinoic acid receptors: From molecular mechanisms to cancer therapy. (February 2015)

• Record Type: Journal Article
• Authors: di Masi, Alessandra; Leboffe, Loris; De Marinis, Elisabetta; Pagano, Francesca; Cicconi, Laura; Rochette-Egly, Cécile; Lo-Coco, Francesco; Ascenzi, Paolo; Nervi, Clara
• Is Part Of: Molecular aspects of medicine. Volume 41(2015)
• Page Start: 1
• Page End: 115
• Publication Date: 2015-02
• Subjects: 4-HPR N-(4-hydroxyphenyl)retinamide -- 5′-UTR 5′-untranslated region -- 9-cis-RA 9-cis retinoic acid -- 9cUAB30 (2E, 4E, 6Z, 8E)-8-(3′, 4′-dihydro-1′(2'H)-naphthalen-1′-ylidene)-3, 7-dimethyl-2, 4, 6-octatrienoic acid -- Acitretin (2E, 4E, 6E, 8E)-9-(4-methoxy-2, 3, 6-trimethylphenyl)-3, 7-dimethylnona-2, 4, 6, 8-tetraenoic acid -- ADA3 activation-3 protein -- AF-1 ligand-independent transcription activating function -- AF-2 ligand-dependent transcription activating function -- AIDA ATRA and Idarubicin -- AKT v-akt murine thymoma viral oncogene homolog 1 -- ALK anaplastic lymphoma receptor tyrosine kinase -- all-trans-RA all-trans retinoic acid -- AM580 4-[(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid -- AM80 4-[[(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl)amino]carbonyl]benzoic acid -- AML acute myeloid leukemia -- AP-1 activator protein-1 -- APL acute promyelocytic leukemia -- ASXL1 additional sex comb-like 1 -- BCC basal cell carcinoma -- BCOR BCL-6 co-repressor -- BMS181156 4-[3-oxo-3-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro- naphthalen-2-yl)-propenyl]-benzoic acid -- BMS184394 6-[(S)-hydroxy(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl)methyl]naphthalene-2-carboxylic acid -- BMS270394 R3-fluoro-4-[[2-hydroxy-2-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8, -tetrahydro-2-naphthalenyl)acetyl]amino]-benzoic acid -- BMS270395 S3-fluoro-4-[[2-hydroxy-2-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8, -tetrahydro-2-naphthalenyl)acetyl]amino]-benzoic acid -- BMS493 4-[(1E)-2-[5, 6-dihydro-5, 5-dimethyl-8-(2-phenylethynyl)-2-naphthalenyl]ethenyl]benzoic acid -- BMS614 4-[[[5, 6-dihydro-5, 5-dimethyl-8-(3-quinolinyl)-2-naphthalenyl]carbonyl]amino]benzoic acid -- BMS649 4-[2-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl)-1, 3-dioxolan-2-yl]benzoate -- BMS753 4-[[(2, 3-Dihydro-1, 1, 3, 3-tetramethyl-2-oxo-1H-inden-5-yl)carbonyl]amino]benzoic acid -- BMS961 3-fluoro-4-[[2-hydroxy-2-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8, -tetrahydro-2-naphthalenyl)acetyl]amino]-benzoic acid -- Bortezomib 3-methyl-1-(3-phenyl-2-pyrazin-2-ylcar-bonylamino-propanoyl) amino-butyl] boronic acid -- BRCA1 breast cancer 1, early onset -- BRD4 bromodomain containing 4 -- CAC1 CDK2-associated cullin 1 -- CCR4 carbon catabolite repressor 4 -- CD437 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid -- CD564 6-[(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl)carbonyl]naphthalene-2-carboxylic acid -- CDK cyclin-dependent kinase -- COUP-TF chicken ovalbumin upstream promoter-transcription factor -- CRABP1 cellular RA binding protein -- CRALBP cellular retinal-binding protein -- CRBP cellular retinoid binding protein -- CREBBP/CBP cAMP response element binding protein-binding protein -- CTCL cutaneous T-cell lymphoma -- CTD C-terminal domain -- CYP26 cytochrome P450, subfamily p26 -- DAXX death-domain associated protein 6 -- DBD DNA binding domain -- DNMT DNA methyl-transferase -- DR direct repeat -- ER estrogen receptor -- E-RABP epididymal RA binding protein -- ERK extracellular signal regulated kinase -- ES cell embryonic stem cell -- ETO RUNX1T1, runt-related transcription factor 1, translocated to, 1 (cyclin D-related) -- FABP5 fatty acid binding protein 5 -- FDA U.S. Food and Drug Administration -- FIPlL1 Fip1-like 1 protein -- FLT3 fms-related tyrosine kinase -- GLEBS Gle2-binding-sequence -- GLFG glycine-leucine-phenylalanine-glycine -- HAT histone acetyl-transferase -- HCC hepatocellular carcinoma -- HDAC histone deacetylase -- HDM histone demethylase -- HER2 human epidermal growth factor receptor-2 -- HMT histone methyl-transferase -- HMW high molecular weight multimeric complex -- HNSCC head and neck squamous cell carcinoma -- hRAR human RAR -- HRE hormone response element -- HSC hematopoietic stem cell -- IFN interferon -- IL interleukin -- IR inverted repeat -- IRBP interphotoreceptor matrix retinoid-binding protein -- ITD internal tandem duplication -- KLF Krüppel-like factor -- KRT keratin -- LBD ligand binding domain -- LBP ligand-binding pocket -- LG100754 (2E, 4E, 6Z)-3-methyl-7-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-3-propoxy-3-naphthalenyl)-2, 4, 6-octatrienoic acid -- lncRNA long noncoding RNA -- Luffariellolide 4-[(3E, 7E)-4, 8-dimethyl-10-(2, 6, 6-trimethyl-1-cyclohexen-1-yl)-3, 7-decadienyl]-5-hydroxy-2(5H)-furanone -- MAPK mitogen-activated protein kinase -- MDS myelodysplastic syndrome -- MF mycosis fungoides -- miRNA microRNA -- MLL-T mixed lineage leukemia -- MM multiple myeloma -- NCoA nuclear receptor co-activator -- NCoR nuclear receptor co-repressor -- ncRNA noncoding RNA -- NK cells natural killer cells -- NMSC non-melanoma skin cancer -- NPM nucleophosmin -- NR nuclear receptor -- NSCLC non-small-cell lung carcinoma -- NTD N-terminal domain -- NuMA nuclear mitotic apparatus protein -- NUP98 nucleoporin 98 -- OBFC2A oligonucleotide/oligosaccharide-binding fold containing -- OCT organic cation transporter 1 -- ORF open reading frame -- PARP poly (ADP-ribose) polymerase -- PcG Polycomb Group -- PHF plant homeodomain D finger -- PKA protein kinase A -- PLZF promyelocytic leukaemia zinc finger protein -- PML promyelocytic leukemia protein -- Pol II RNA Polymerase II -- PPAR peroxisome proliferator-activated receptor -- PRAME preferentially expressed antigen in melanoma -- pRb phospho- retinoblastoma -- PRC Polycomb group repressive complex -- PRKAR1A cAMP-dependent protein kinase type Iα regulatory subunit -- PTCH1 patched homologue 1 -- PTOV1 prostate tumor overexpressed 1 -- RA retinoic acid -- RAE retinol activity equivalents -- RALDH retinaldehyde dehydrogenase -- RAR retinoic acid receptor -- RARA gene encoding RARα -- RARB gene encoding RARβ -- RARE RA response element -- RARG gene encoding RARγ -- RBCC RING-B-box-coiled-coil -- RBP retinol binding protein -- RCC renal cell carcinoma -- RXR retinoid X receptor -- SCC squamous cell carcinoma -- SIRT sirtuin -- SMRT silencing mediator of retinoic acid and thyroid hormone receptor -- SNP single nucleotide polymorphism -- SR11254 6-[(1Z)-(hydroxyimino)(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl)methyl]naphthalene-2-carboxylic acid -- SRC steroid receptor co-activator -- SS Sézary syndrome -- Stat5 signal transducer and activator of transcription 5 -- T3 triiodothyronine -- TAF TATA box associated factor -- TBL1 transducin β-like1 -- TBLR1 transducin β-like1 X-linked receptor 1 -- TCR T-cell receptor -- TFIID TATA box binding protein -- TFIIH general transcription factor IIH -- TR thyroid receptor -- TRAP220 thyroid receptor-associated protein complex 220 kDa component -- VAD vitamin A-deficient diet -- VDR vitamin D receptor -- VEGF vascular endothelial growth factor -- VPA valproic acid -- WBC white blood cells -- XP xeroderma pigmentosum; 13-cis retinoic acid -- all-trans retinoic acid -- Cancer -- Cancer prevention -- Development -- Differentiation -- Genomic effects -- Leukemia -- Non-genomic effects -- Nuclear receptor -- RAR -- Retinoids -- RXR -- Signaling -- Structure -- Transcription; Pathology, Molecular -- Periodicals; Medicine -- Periodicals; Biochemistry -- Periodicals; Medicine -- Periodicals; Molecular Biology -- Periodicals; Pathologie moléculaire -- Périodiques; Médecine -- Périodiques; Electronic journals; 612.015
• DOI: 10.1016/j.mam.2014.12.003
• Languages: English
• ISSNs: 0098-2997

Abstract

Abstract: Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.