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PubMed1998

Retinoid receptors expression in human term placenta: involvement of RXR alpha in retinoid induced-hCG secretion.

To investigate the role of retinoids on human placental development and functions, we characterized the spatial distribution of retinoid receptors in human term chorionic villi. In situ hybridization with 35S labeled sense and antisense probes for the RARs, alpha, beta, gamma and RXRs, alpha, beta, gamma, specifically detected only RAR alpha and RXR alpha. Both RAR alpha and RXR alpha mRNA were preferentially expressed in the trophoblast cell layer. This syncytiotrophoblast expression was confirmed by immunohistochemical analyses using anti-RAR alpha and RXR alpha antibodies. Using trophoblast cells in culture, we then studied the effect on hCG secretion of 0.1 microM RA physiological forms and of selective RAR alpha and RXR alpha synthetic agonists. Only RXR alpha specific ligands such as physiological 9-cis RA and synthetic Ro 25-7386 stimulated hCG secretion (doubled). These results suggest an important role for RXR alpha in human placental development and function.

Cells, Cultured↗

PubMed2006

Acyclic retinoid, a novel synthetic retinoid, induces growth inhibition, apoptosis, and changes in mRNA expression of cell cycle- and differentiation-related molecules in human colon carcinoma cells.

Acyclic retinoid (ACR), a novel synthetic retinoid, has been demonstrated by us to inhibit the in vitro growth of human hepatoma cells, and this effect was associated with modification of cell cycle control molecules, suggesting that this agent may be useful in the chemoprevention and therapy of various types of malignancies. However, whether or not ACR exerts anticancer activities on human colon carcinoma cells has not yet been elucidated. The purpose of this study was to examine the inhibitory effects of ACR in human colon carcinoma cells and to characterize the molecular mechanism of action of this agent. ACR inhibited the growth of the HCT116 and SW480 human colon carcinoma cell lines with IC50 values of about 30 and 60 microM, respectively. ACR also induced G1-phase cell cycle arrest and apoptosis in these cell lines. When the HCT116 cells were treated with 5-25 microM ACR, there was a marked decrease in the cellular levels of cyclin D1 mRNA and an approximate 2.5- to 3-fold increase in those of p21CIP1 mRNA, and this induction occurred via a p53-independent mechanism. Furthermore, ACR induced a dose-dependent mRNA elevation of differentiation markers at concentrations of ACR that affect the levels of expression of p21CIP1. These novel results suggest that ACR inhibits cell proliferation by inducing G1 arrest and apoptosis and that cyclin D1 and p21CIP1 play critical roles in the molecular mechanisms of growth inhibition and differentiation induced by ACR. Collectively, these findings provide further evidence that ACR may be a potential agent for the chemoprevention and therapy of human colon cancer.

Antineoplastic Agents↗

PubMed1980

Comparison of the level of cellular retinoid-binding proteins and susceptibility to retinoid-induced growth inhibition of various neoplastic cell lines.

The presence and level of cellular retinol-binding protein (CRBP) and cellular retinoic acid-binding protein (CRABP) were determined in several neoplastic cell lines. These cells exhibited different degrees of susceptibility to growth inhibition in culture by two retinoids, retinyl acetate and retinoic acid. CRABP was detected in 10 and CRBP in 3 of the 11 tested cell lines. The levels of CRBP and CRABP were in the ranges 15-3,400 and 4-1,290 pmol per 10(9) cells, respectively, as determined by sucrose gradient centrifugation. Cell lines that contained CRABP included S91 and B16 melanomas; Mm5mT and DMBA No. 8 mammary adenocarcinomas; BW5147, BW5147.RicR, and P3 neoplastic lymphoid cells; F361.2 (a hybrid cell line obtained by fusion of MSV3T3 and BW5147); MSV3T3 sarcoma; and RAW8 lymphosarcoma. All but the last two cell lines were inhibited by retinoic acid in culture. CRBP was detected in extracts of S91, Mm5mT, and RAW8. Retinyl acetate inhibited the growth of all cell lines with the exception of RAW8, MSV3T3, and F361.2. No correlation was found between the level of either binding protein and the extent of growth inhibition by either retinyl acetate or retinoic acid. Neither of the binding proteins was detected in L1210-A5 leukemia cells, whose proliferation can be inhibited by both retinyl acetate and retinoic acid. These data indicated that screening cell lines for the presence and level of CRBP and CRABP is not sufficient to predict the susceptibility of cultured cells to growth inhibition by retinoids.

Adenocarcinoma↗

PubMed2005

Aza-retinoids as novel retinoid X receptor-specific agonists.

A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.

Aza Compounds↗

PubMed1998

Expression of retinoic acid receptor and retinoid X receptor subtypes in rat liver cells: implications for retinoid signalling in parenchymal, endothelial, Kupffer and stellate cells.

In the present study, a systematic examination of the relative expression pattern of the nuclear retinoid receptors (RAR and RXR) in various liver cells was performed. Our data demonstrate that RXRalpha is the dominant receptor in all liver cells, and that RARbeta is also expressed at a high level in most cells. More specifically, RARbeta and RARalpha were the most predominant of the RAR subtypes in parenchymal cells, while all three RAR subtypes were equally expressed in endothelial and Kupffer cells. The total level of expression of all the RXR subtypes were larger than the total level of expression of all the RAR subtypes in all liver cells. This is in agreement with the observation that RXR is a heterodimer partner not only for RAR, but also for other members in the steroid/thyroid receptor superfamily of ligand-dependent transcription factors.

Animals↗

PubMed2003

Effects of retinoid ligands on RIP140: molecular interaction with retinoid receptors and biological activity.

Receptor interacting protein 140 (RIP140) interacts with retinoic acid receptor (RAR) and retinoid X receptor (RXR) constitutively, but hormone binding enhances this interaction. The ligand-independent interaction is mediated by the amino and central regions of RIP140 which contain a total of nine copies of the LXXLL motif, whereas the agonist-induced interaction is mediated by its carboxyl terminus which contains a novel motif (1063-1076, LTKTNPILYYMLQK). The ligand-independent interaction could be enhanced slightly by agonists, whereas the ligand-dependent interaction was strictly agonist dependent for both RAR and RXR. In the context of heterodimers, ligand occupancy of RXR played a more dominant role for both molecular interaction and biological activity of RIP140. Competition and mutation studies demonstrated an essential role for (1067)Asn and (1073)Met for a ligand-dependent interaction. A model was proposed to address the constitutive and agonist-dependent interaction of RIP140 with RAR/RXR.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Synthesis of novel retinoid X receptor-selective retinoids.

Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl(3)-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl(3)-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethylterephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH(2)OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.

Receptors, Retinoic Acid↗

PubMed1997

Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family.

Dopamine is a neuromodulator involved in the control of key physiological functions. Dopamine-dependent signal transduction is activated through the interaction with membrane receptors of the seven-transmembrane domain G protein-coupled family. Among them, dopamine D2 receptor is highly expressed in the striatum and the pituitary gland as well as by mesencephalic dopaminergic neurons. Lack of D2 receptors in mice leads to a locomotor parkinsonian-like phenotype and to pituitary tumors. The D2 receptor promoter has characteristics of a housekeeping gene. However, the restricted expression of this gene to particular neurons and cells points to a strict regulation of its expression by cell-specific transcription factors. We demonstrate here that the D2 receptor promoter contains a functional retinoic acid response element. Furthermore, analysis of retinoic acid receptor-null mice supports our finding and shows that in these animals D2 receptor expression is reduced. This finding assigns to retinoids an important role in the control of gene expression in the central nervous system.

Animals↗

PubMed2004

Retinoid X receptor-gamma and peroxisome proliferator-activated receptor-gamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment.

Poorly differentiated, metastatic thyroid cancer is difficult to treat. These tumors often do not concentrate radioactive iodine and may require chemotherapy, which is suboptimal and toxic. Nuclear hormone receptors peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid X receptor (RXR) are variably expressed in thyroid carcinoma cell lines. Expression of these receptors may predict thyroid cancer cell response to treatment with rexinoids and thiazolidinediones. We studied three thyroid carcinoma cell lines: BHP 5-16 (PPARgamma-/RXRgamma+), BHP 2-7 (PPARgamma+/-/RXRgamma-), and DRO-90 (RXRgamma+/PPARgamma+). BHP 5-16 (RXRgamma+) cells treated with rexinoid had decreased proliferation to 69 +/- 6% growth compared with vehicle. BHP 2-7 (PPARgamma+) cells treated with thiazolidinedione had no decrease in cellular proliferation. DRO-90 (RXRgamma+ and PPARgamma+) cells had 36 +/- 10%, 15 +/- 3%, and 13 +/- 4% growth when treated with rexinoid, thiazolidinedione, or a combination, respectively. We next investigated the role of apoptosis in the ligand-responsive BHP 5-16 and DRO-90 cells. BHP 5-16 cells underwent no significant apoptosis with rexinoid (1 micromol/L). DRO-90 cells, however, had 3.6 +/- 1.3% apoptotic cells with vehicle, 13 +/- 3.5% with rexinoid (1 micromol/L), 18 +/- 4% with thiazolidinedione (1 micromol/L), and 28 +/- 6% with combination treatment (1 micromol/L), suggesting that apoptosis plays a major role in this anaplastic cell line and that the effects of the two ligands are additive. We conclude that receptor expression is necessary for inhibition of thyroid carcinoma growth with ligand treatment but may not be sufficient for response. Additionally, expression of both RXRgamma and PPARgamma may be necessary for maximal growth inhibition by ligands and may be required for the increased apoptosis.

Apoptosis↗

PubMed1998

Cloning of crustacean ecdysteroid receptor and retinoid-X receptor gene homologs and elevation of retinoid-X receptor mRNA by retinoic acid.

We report the cloning and analysis of ecdysteroid receptor (bpEcR) and retinoid-X receptor (UpRXR) cDNA homologs from the fiddler crab Uca pugilator. The deduced amino acid sequence of this crustacean EcR most closely resembles the insect EcRs within the DNA binding and ligand binding domains (LBDs). For UpRXR, the DNA binding domain (DBD) shares greatest identity to the insect USPs. The ligand binding domain, however, is closer to vertebrate RXRs but may have a nonfunctional AF-2 domain. Probes derived from these clones were used to examine transcript levels in blastemas during early limb regeneration. Both UpEcR and UpRXR transcripts were detected in low amounts 1 day after limb loss, but increased during the next 4 days. Immersion of crabs in sea water containing all-trans retinoic acid increased the steady state concentrations of UpRXR transcript and altered the pattern of circulating ecdysteroids. These effects correlate with the disruptive effects of retinoic acid on blastemal differentiation observed in earlier studies.

Amino Acid Sequence↗

PubMed2001

Structure-Activity study of retinoid agonists bearing substituted dicarba-closo-dodecaborane. Relation between retinoidal activity and conformation of two aromatic nuclei.

We have investigated the structure activity relationships of the potent retinoid agonist, 4-[4-(2-propyl-1,2-dicarba-closo-dodecaboran-l-yl)phenylamino]benzoic acid (BR403), which we have previously reported. Substitution of a methyl group on the aromatic nucleus or a methyl group on the nitrogen atom, or replacement of the amino group with ether, methylene, carboxyl or 1,1-ethylene greatly decreased the activity. The relatively planar conformation at the phenyl-N-phenyl moiety seems to play a critical role in the appearance of the biological activity.

Animals↗

PubMed2002

Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions.

Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.

2-Naphthylamine↗

PubMed1998

Critical role of both retinoid nuclear receptors and retinoid-X-receptors in mediating growth inhibition of ovarian cancer cells by all-trans retinoic acid.

Retinoids have been shown to inhibit the growth of a number of human tumor cells, including several ovarian adenocarcinoma cell lines. All-trans retinoic acid (RA) is an effective growth suppressor of CA-OV3 cells but not SK-OV3 cells. Since the effects of RA are known to be mediated via the nuclear receptors (RARs and RXRs), we initially compared levels of the various RARs and RXRs in the CA-OV3 and SK-OV3 cell lines. The RA resistant SK-OV3 cells expressed reduced levels of RAR-alpha and RXR-alpha. Furthermore, induction of RAR-alpha by RA was impaired in the RA resistant SK-OV3 cells as was RARE binding and RARE-dependent transcriptional activity. These results suggested that changes in the amounts and/or activity of RARs and/or RXR-alpha could determine the growth response of ovarian tumor cells to RA. This was confirmed by modulating the levels of RARs and RXR-alpha in the SK-OV3 cells using the LacSwitch inducible expression system. Stably transfected clones of RA resistant SK-OV3 cells exhibited a significant inhibition of growth by RA treatment when RAR-alpha was induced. Overexpression of both RAR-alpha and RXR-alpha resulted in a level of growth inhibition nearly equal to that exhibited by the RA sensitive CA-OV3 cell line. Similar results were obtained when a combination of RXR-alpha and either RAR-beta or RAR-gamma was overexpressed in SK-OV3 cells. Our results show that the nuclear receptors and RXR-alpha play a critical role in mediating growth suppression by RA in ovarian cancer cells.

Blotting, Western↗

PubMed1992

Multiple retinoid-responsive receptors in a single cell: families of retinoid "X" receptors and retinoic acid receptors in the Xenopus egg.

In a search for nuclear hormone receptors expressed in early development we found that Xenopus laevis eggs contain mRNAs from two retinoic acid receptor genes (xRAR alpha and xRAR gamma) and two retinoid "X" receptor genes (xRXR alpha and xRXR gamma). We also show that RXRs are members of a family of at least three genes, thus expanding the number of genes encoding retinoic acid-responsive transcription factors to six. With the exception of xRXR gamma, these maternal mRNAs are degraded before gastrulation. The RXRs isolated are differentially activated by retinoic acid and by 3,4-didehydroretinoic acid. Considered together, these four receptors provide a molecular basis for the pleiotropic effects of retinoic acid on early development, and their pattern of expression suggests a role for retinoic acid at the earliest stages of embryonic determination.

Amino Acid Sequence↗

PubMed1998

IkappaBbeta interacts with the retinoid X receptor and inhibits retinoid-dependent transactivation in lipopolysaccharide-treated cells.

To elucidate the molecular action of the NFkappaB inhibitor IkappaBbeta, we isolated a number of IkappaBbeta interactors using the yeast two-hybrid system. These include the retinoid X receptor (RXR), whose interaction with IkappaBbeta is significantly stimulated by the RXR ligand 9-cis-retinoic acid, as shown in the yeast system as well as the glutathione S-transferase pull down assays. RXR is a nuclear protein, whereas IkappaBbeta accumulates in the nucleus only in cells stimulated with lipopolysaccharide or other inducers that result in prolonged activation of NFkappaB. Consistent with this, cotransfection with IkappaBbeta specifically repressed the 9-cis-RA-induced transcriptional activities of RXR in an lipopolysaccharide-dependent manner. These results suggest a novel IkappaBbeta-mediated antagonism between the signaling pathways of NFkappaB and RXR.

Alitretinoin↗

PubMed1993

The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.

Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.

Animals↗

PubMed1995

Retinoids, retinoic acid receptors, and cytoplasmic retinoid binding proteins in perinatal rat lung fibroblasts.

The early postnatal life of most mammals marks a period of extensive enlargement of the alveolar surface area and increase in the elastin content of the lung. The factors that regulate the onset and abatement of this burst of elastin synthesis have not been identified. Previous studies of lipid-laden rat pulmonary interstitial fibroblasts (LIF) have shown that their elastin synthesis is increased in vitro by retinoic acid (RA). We hypothesized that temporal changes in the endogenous RA content of LIF may correlate with changes in elastin synthesis by these cells. LIF were isolated from the lungs of rats at gestational day 19 and postnatal days 2, 4, 8, and 12 and their retinoid contents were quantitated. Retinyl esters were highest at gestational day 19 (2.9 +/- 0.6 pmol/10(6) cells, means +/- SE) and decreased to 1.6 +/- 0.2 pmol by postnatal day 2 (P < 0.05). This decrease in retinyl esters was accompanied by an increase in retinol from 0.4 +/- 0.1 to 2.0 +/- 0.6 pmol/10(6) cells (P < 0.05). RA increased in LIF from 0.07 +/- 0.04 pmol/10(6) cells at gestational day 19 to 0.29 +/- 0.05 pmol/10(6) cells at postnatal day 2 (P < 0.05) and increased in whole lung tissue from 0.07 +/- 0.04 to 0.29 +/- 0.05 nmol/g, over the same interval. The increase in RA content was accompanied by an increase in RA receptor (RAR)-beta and -gamma mRNAs. The steady-state mRNA level of cellular retinol binding protein (CRBP) was high in LIF, relative to whole lung tissue at day 2. Cellular RA binding protein (CRABP) mRNA rose fourfold from day 2 to day 8 and then fell by day 12. In summary, RA, RAR, and CRBP mRNA in LIF are highest before the period of maximal elastin synthesis, which occurs at postnatal days 8 and 12. These findings are consistent with the hypothesis that endogenous RA could contribute to the postnatal increase in elastin production by pulmonary fibroblasts.

Aging↗

PubMed1997

[Study on the structure-activity relationships of retinoids. II. 3D-QSAR of retinoids and receptor interaction].

Precise prediction of the binding constant of ligand to receptor is an important aspect of structure-based drug design. Almost all methods including de novo design and 3D database search are over concentrated on structure generation rather than quantitative evaluation of the binding properties of the newly produced molecule. Using epididymal retinoic acid binding protein (ERABP) as a model, we simulated the interaction between retinoids and their receptor with DOCK program and obtained an equation for predicting the binding constants. According to the docking conformers of the ligands, CoMFA was also used to deduce a pharmacophoric model of this series of compound.

Receptors, Retinoic Acid↗