title: Retinoic acid receptors: from molecular mechanisms to cancer therapy.
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.
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Roma I-00146, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: di Masi
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Roma I-00146, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: Leboffe
authors.affiliation: Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: De Marinis
authors.affiliation: Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pagano
authors.affiliation: Department of Biomedicine and Prevention, University of Roma "Tor Vergata", Via Montpellier 1, Roma I-00133, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Via Ardeatina, 306, Roma I-00142, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cicconi
authors.affiliation: Department of Functional Genomics and Cancer, IGBMC, CNRS UMR 7104 - Inserm U 964, University of Strasbourg, 1 rue Laurent Fries, BP10142, Illkirch Cedex F-67404, France. Electronic address: cegly@igbmc.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Rochette-Egly
authors.affiliation: Department of Biomedicine and Prevention, University of Roma "Tor Vergata", Via Montpellier 1, Roma I-00133, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Via Ardeatina, 306, Roma I-00142, Italy. Electronic address: francesco.lo.coco@uniroma2.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.affiliation: Interdepartmental Laboratory for Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, Roma I-00146, Italy. Electronic address: ascenzi@uniroma3.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ascenzi
authors.affiliation: Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100. Electronic address: clara.nervi@uniroma1.it.
authors.forename: Clara
authors.initials: C
authors.lastname: Nervi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C082925:retinoic acid receptor beta
keywords: 13-cis retinoic acid; Cancer; Cancer prevention; Development; Differentiation; Genomic effects; Leukemia; Non-genomic effects; Nuclear receptor; RAR; RXR; Retinoids; Signaling; Structure; Transcription; all-trans retinoic acid