The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid × receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with the emphasis on the application of retinoids in cancer treatment and prevention. KeywordsRetinoids; Nuclear receptor; RAR; RXR; all-trans retinoic acid; 9-cis retinoic acid; 13-cis retinoic acid HistoryVitamin A and its derivatives (retinoids) exert a wide range of effects on embryonic development, cell growth, differentiation, and apoptosis. Vitamin A has been used as a treatment for thousands of years. The Egyptian papyruses Kahun 1 (ca. 1825 B.C.) and Ebers (ca. 1500 B.C.) described how the liver was used to cure eye diseases such as night blindness. Greek scholar Hippocrates (460-327 B.C.) described in the second book of "Prognostics" a method for curing night blindness: "raw beef liver, as large as possible, soaked in honey, to be taken once or twice by mouth." Chinese medicine used pigs' liver as a remedy for night blindness, as described by Sun-szu-mo (7th century A.D.) in his "1000 Golden Remedies". Given that the liver is where the body stores excess vitamin A, the liver represents the best source of vitamin A available for treatment in the pre-pharmaceutical world.One of the first experiments involving vitamin A was performed by F. Magendie (1817) [1], in which he fed dogs a diet of only sugar and water. Three weeks later, the dogs got sick and developed ulcers of the cornea. At the time, Magendie attributed these effects to nitrogen * Corresponding Author: Yu-Jui Yvonne Wan, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, Phone: 1-913-588-9111, Fax: 1-913-588-7501, ywan@kumc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptAdv Drug Deliv Rev. Author manuscript; available in PMC 2011 October 30. NIH-PA Author Manusc...
One mode of ␥-globin gene silencing involves a GATA-1⅐FOG-1⅐Mi2 repressor complex that binds to the ؊566 GATA site relative to the A ␥-globin gene cap site. However, the mechanism of how this repressor complex is assembled at the ؊566 GATA site is unknown. In this study, we demonstrate that the O-linked N-acetylglucosamine (O-GlcNAc) processing enzymes, O-GlcNAc-transferase (OGT) and O-GlcNAcase (OGA), interact with the A ␥-globin promoter at the ؊566 GATA repressor site; however, mutation of the GATA site to GAGA significantly reduces OGT and OGA promoter interactions in -globin locus yeast artificial chromosome (-YAC) bone marrow cells. When WT -YAC bone marrow cells are treated with the OGA inhibitor Thiamet-G, the occupancy of OGT, OGA, and Mi2 at the A ␥-globin promoter is increased. In addition, OGT and Mi2 recruitment is increased at the A ␥-globin promoter when ␥-globin becomes repressed in postconception day E18 human -YAC transgenic mouse fetal liver. Furthermore, we show that Mi2 is modified with O-GlcNAc, and both OGT and OGA interact with Mi2, GATA-1, and FOG-1. Taken together, our data suggest that O-GlcNAcylation is a novel mechanism of ␥-globin gene regulation mediated by modulating the assembly of the GATA-1⅐FOG-1⅐Mi2 repressor complex at the ؊566 GATA motif within the promoter.
Fenretinide, a synthetic retinoid, is known to induce apoptosis in various cancer cells. However, the mechanism by which fenretinide induces apoptosis remains unclear. The current study examines the mechanisms of fenretinide-induced apoptosis in human hepatoma cells. The induction of Nur77 and the cytoplasmic distribution of Nur77 induced by fenretinide were positively correlated with the apoptotic effect of fenretinide in HCC cells. The sensitivity of Huh-7 cells was related to Nur77 translocation and targeting mitochondria, whereas the mechanism of resistance for HepG2 cells seemed due to Nur77 accumulating in the nucleus. The intracellular location of Nur77 was also associated with the differential capability of fenretinide-induced ROS generation in these two cell lines. In addition, the knockdown of Nur77 expression by siRNA greatly reduced fenretinide-induced apoptosis and cleaved caspase3 in Huh7 cells. Therefore, our findings demonstrate that fenretinideinduced apoptosis of HCC cells is Nur77 dependent and that the intracellular localization of Nur77 dictates the sensitivity of the HCC cells to fenretinide-induced apoptosis.
Due to their well-known differentiation and apoptosis-inducing abilities, retinoic acid (RA) and its analogs have strong anti-cancer efficacy in human cancers. However, in vivo RA is a liver mitogen. While speculation has persisted that RA-mediated signaling is likely involved in hepatocyte proliferation during liver regeneration, direct evidence is still required. Findings in support of this proposition include observations that a release of retinyl palmitate (the precursor of RA) occurs in liver stellate cells following liver injury. Nevertheless, the biological action of this released vitamin A is virtually unknown. More likely is that the released vitamin A is converted to RA, the biological form, and then bound to a specific receptor (retinoid x receptor; RXRα), which is most abundantly expressed in the liver. Considering the mitogenic effects of RA, the RA-activated RXRα would likely then influence hepatocyte proliferation and liver tissue repair. At present, the mechanism by which RA stimulates hepatocyte proliferation is largely unknown. This review summarizes the activation of nuclear receptors (peroxisome proliferator activated receptor-α, pregnane x receptor, constitutive androstane receptor, and farnesoid x receptor) in an RXRα dependent manner to induce hepatocyte proliferation, providing a link between RA and its proliferative role.
Fenretinide [N‐(4‐hydroxyphenyl) retinamide] is a synthetic analog of all‐trans retinoic acid (RA). We have previously shown that fenretinide, but not all‐trans RA, induced apoptosis in Huh7 cells, a human hepatocellular carcinoma (HCC) cell line. While previous data shows that both differentiation and apoptosis are mediated through a retinoic acid receptor β (RARβ)‐dependent manner, the mechanisms by which fenretinide and all‐trans RA exert their different roles are not well understood. Our data showed that both chemicals induced RARβ mRNA and protein levels as well as activated ERK1/2 and Akt within 3 hrs. Both chemicals also induced the expression level of LC3. However, the conversion of LC3‐I to LC3‐II, a hallmark of autophagy, was substantially higher in all‐trans RA than fenretinide‐treated cells. In addition, the level of signaling adaptor p62, which is crucial for activation of death receptors and caspase 8‐mediated apoptosis, was significantly lower in all‐trans RA than fenrentinide‐treated Huh7 cells. Consequentially, fenretinide, but not all‐trans RA, caused ROS accumulation in Huh7 cells, which in turn lead to apoptosis. Taken together, the differential autophagy induction and p62 degradation might account for the different effect of all‐trans RA and fenretinide in controlling the survival or death of HCC cells.
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