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.
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Several semi-synthetic and synthetic retinoids have been developed to decrease the toxicity of natural retinoids and to increase their stability and selectivity against a specific RAR subtype.
“To decrease the toxicity of the natural retinoids as well as to increase their stability and selectivity against a specific RAR subtype, several semi-synthetic and synthetic retinoids (including “atypical retinoids”) have been developed29,30.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [30]
At least four molecules have reached phase 4 clinical trials: bexarotene, tazarotene, adapalene, and trifarotene.
“At least four molecules have reached phase 4 clinical trials: bexarotene, tazarotene, adapalene, and trifarotene29–31.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [30]
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Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine
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- Authors
- di Masi, A., Leboffe, L., De Marinis, E., Pagano, F., Cicconi, L., Rochette-Egly, C., Lo-Coco, F., Ascenzi, P., & Nervi, C.
- Affiliations
- Roma Tre University (IT)
- Sapienza University of Rome (IT)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Ascenzi, Paolo
- Nervi, Clara
- Venue
- Molecular Aspects of Medicine
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 41
- Pages
- 1-115
- ISSN
- 0098-2997 (ISSN-L)
- OpenAlex
- W2064402415
- Cited by
- 403
- References
- 1,342
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 50 · 2023: 32 · 2022: 44 · 2021: 42 · 2020: 41 · 2019: 41 · 2018: 31 · 2017: 24 · 2016: 30 · 2015: 12
- FWCI
- 9.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Aspects of Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Iris (Roma Tre University) (submittedVersion)
- Funders
- Italian Association for Cancer Research
- Italian Foundation for Cancer Research (15142)
- University of Roma “La Sapienza”
- Fondazione Roma
- CNRS
- INSERM
- Agence Nationale pour la Recherche (ANR-05-BLAN-0390-02, ANR-09-BLAN-0297-01)
- Foundation pour la Recherche Medicale (DEQ20090515423)
- Institut National du Cancer (INCa-PLO7-96099, PL09-194)
- Association pour la Recherche sur le Cancer (3169, SL220110603474)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- retinoic acid receptor, retinoic acid signaling, retinoid X receptor, nuclear receptor superfamily, transcriptional regulation, non-genomic signaling, retinoids, cancer therapy, chemoprevention, leukemia, skin cancer, head and neck cancer, lung cancer, breast cancer, prostate cancer, differentiation therapy, apoptosis
- MeSH terms
- Retinoic Acid Receptor alpha, Retinoic Acid Receptor gamma, Animals, Antineoplastic Agents, Female, Humans, Male, Neoplasms, Tretinoin, Receptors, Retinoic Acid, Response Elements
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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