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At least 19 recordsLinked to original sources
PubMed2005

Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms.

We have investigated the role of Vitamin A (retinoid) proteins in hepatic retinoid processing under normal conditions and during chemical stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a chemical known to interfere with retinoid turnover and metabolism. Three separate studies were performed in wildtype control mice and transgenic mice that lack one or more isoforms of retinoic acid receptors (RAR), retinoid X receptors (RXR), or intracellular retinoid-binding proteins (CRABP I, CRABP II, CRBP I). Body and organ weight development was monitored from 2 weeks of age to adult, and hepatic levels of retinyl esters, retinol, and retinoic acid were investigated. In addition, hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid, a recently discovered retinoid metabolite that has proven sensitive to both TCDD exposure and Vitamin A status, were also determined. Mice absent in the three proteins CRBP I, CRABP I, and CRABP II (CI/CAI/CAII-/-) displayed significantly lower hepatic retinyl ester, retinol, and all-trans-retinoic acid levels compared to wildtype mice, whereas the liver concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid was considerably higher. After treatment with TCDD, hepatic total retinoids were almost entirely depleted in the CI/CAI/CAII-/- mice, whereas wildtype mice and mice lacking CRABP I, and CRABP II (CAI/CAII-/-) retained approximately 60-70% of their Vitamin A content compared to controls at 28 days. RAR and RXR knockout mice responded similarly to wildtype mice with respect to TCDD-induced retinoid disruption, with the exception of RXRbeta-/- mice which showed no decrease in hepatic Vitamin A concentration, suggesting that the role of RXRbeta in TCDD-induced retinoid disruption should be further investigated. Overall, the abnormal retinoid profile in the triple knockout mice (CI/CAI/CAII-/-), but not double knockout (CAI/CAII-/-) mice, suggests that a loss of CRBP I may account for the difference in retinoid profile in CI/CAI/CAII-/- mice, and is likely to result in an increased susceptibility to hepatic retinoid depletion following dioxin exposure.

Animals↗
PubMed1988

Specific uptake of retinoids into human promyelocytic leukemia cells HL-60 by retinoid-specific binding protein: possibly the true retinoid receptor.

The uptake of all-trans-retinoic acid (RA) and two new retinoids [4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl )benzoic acid (Am80) and (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid (Ch55)] by HL-60 human promyelocytic leukemia cells was investigated. For the investigation, [3H]RA and [3H]Am80 with high specific radioactivities (more than 50 Ci/mmol) were used. [3H]Am80 was prepared by hydrogenolysis of the corresponding chlorinated derivative of Am80 with tritium gas. The retinoids RA, Am80 and Ch55 were efficiently taken up by HL-60 cells, and induced differentiation of the cells into mature granulocytes. The specific bindings (uptake) of RA, Am80 and Ch55 (the bindings inhibited competitively by the other two retinoids) by HL-60 cells were due to a newly detected binding protein. The protein that bound specifically to RA appeared identical to that which bound specifically to Am80 by high-performance liquid chromatography (HPLC), and was named retinoid-specific binding protein (RSBP). One HL-60 cell was found to contain about 1500 molecules of RSBP distributed between the nuclear fraction and cytosolic fraction in proportions of about 4:1. The bindings of the three retinoids (RA, Am80 and Ch55) to RSBP (i.e., formation of retinoid-RSBP complexes) greatly enhanced the affinity of RSBP for the nuclei. The apparent molecular weight of RSBP was estimated to be 95,000 daltons by size exclusion HPLC. The association constants (Ka) of RSBP were calculated to be 2.4 X 10(10) M-1 for RA and 4.4 X 10(10) M-1 for Am80 from Scatchard plots. The bindings of RA, Am80 and Ch55 to RSBP were mutually competitive, indicating that the binding sites for RA, Am80 and Ch55 were identical. The very high affinities of these retinoids for RSBP (Ka's of the order of 10(10) M-1) correspond to the effective concentrations of these retinoids in HL-60 cell culture medium for induction of differentiation of the cells. The mutually competitive bindings of these retinoids strongly support the idea that RSBP is the true receptor of retinoids.

Benzoates↗
PubMed1998

Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.

Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C-III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (80 mg/d; 5 d) resulted in elevated plasma apo C-III, but not apo E concentrations. In human hepatoma HepG2 cells, retinoids increased apo C-III mRNA and protein production. Transient transfection experiments indicated that retinoids increase apo C-III expression at the transcriptional level. This increased apo C-III transcription is mediated by the retinoid X receptor (RXR), since LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8, 8-pentamethyl-2-naphtalenyl)ethenyl]benzoic acid), a RXR-specific agonist, but not TTNPB ((E)- 4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphtalenyl)propenyl]benzoic acid), a retinoic acid receptor (RAR)-specific agonist, induced apo C-III mRNA in HepG2 cells and primary human hepatocytes. Mutagenesis experiments localized the retinoid responsiveness to a cis-element consisting of two imperfect AGGTCA sequences spaced by one oligonucleotide (DR-1), within the previously identified C3P footprint site. Cotransfection assays showed that RXR, but not RAR, activates apo C-III transcription through this element either as a homo- or as a heterodimer with the peroxisome proliferator-activated receptor. Thus, apo C-III is a target gene for retinoids acting via RXR. Increased apo C-III expression may contribute to the hypertriglyceridemia and atherogenic lipoprotein profile observed after retinoid therapy.

Adult↗
PubMed1995

Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.

The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three RAR subtypes or RXR alpha. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha activity and selectivity. In addition, the beta-geranylidene and 20-methyl-(11E,13E)-dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXR alpha selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5-thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.

Cell Line↗
PubMedDate not supplied

Distribution of endogenous retinoids, retinoid binding proteins (RBP, CRABPI) and nuclear retinoid X receptor beta (RXRbeta) in the porcine embryo.

Retinoids are important signalling molecules in the development of limbs and in the determination of the anterior-posterior orientation of the embryo. The present study examined the content and distribution of retinoic acid, retinol and retinyl esters in porcine embryos during early gestation (gestation days 22-30) macroscopically and microscopically by its autofluorescence and by HPLC. Macroscopically, the yellowish-greenish autofluorescence characteristic of vitamin A was observed in tissues affected by morphogenesis, such as the limbs, in a spatial and temporal manner. Changes in the intensity of autofluorescence in the limbs paralleled changes in the concentration of retinoids in these structures. In the limbs and the body, retinol, retinyl palmitate, and all-trans-retinoic acid but neither the isomers of all-trans retinoic acid nor other retinoid metabolites were detected. In addition, the distribution of specific retinoid-binding proteins was investigated; these are involved in vitamin A transport, metabolism and signal transduction. Immunoreactive retinol-binding protein as well as cellular retinoic acid binding protein type I were only localised in the mesonephros, while the retinoid X receptor beta was widely distributed in most of the tissues and organs of the embryo throughout the time period investigated. The combination of autofluorescence and HPLC analysis allowed for the first time to attribute the yellowish-greenish autofluorescence in specific regions of the embryo to vitamin A, and offers a method to study the local cellular distribution of retinol and/or retinyl esters as well as their concentrations in embryonic tissues.

Animals↗
PubMed1997

Effect of retinoid status on the messenger ribonucleic acid expression of nuclear retinoid receptors alpha, beta, and gamma, and retinoid X receptors alpha, beta, and gamma in the mouse testis.

The testicular gene expression of the retinoic acid receptors, RAR alpha, -beta, and -gamma, was studied in normal mice and in vitamin A-deficient mice after the administration of all-trans-retinoic acid (ATRA). All three types of RARs were expressed in normal and/or vitamin A-deficient testes. Only the expression of RAR beta messenger RNA was transiently induced within 24 h after ATRA injection. ATRA-induced RAR beta expression was also found in purified Sertoli cells, suggesting that these cells mediate at least part of the effect of retinoids on germ cells. When an equimolar amount of retinol was administered instead of ATRA, no induction of RAR beta was seen at the point of maximal induction by ATRA, suggesting that the effect of retinol was delayed and probably less. The related nuclear receptors, RXR alpha, -beta, and, for the first time, gamma, were also shown to be present in the mouse testis. Upon administration of ATRA, messenger RNA expression of RXR alpha and -beta did not change significantly. The expression of RXR gamma was too low to allow quantification. Finally, the effect of the retinoid metabolism inhibitor liarozole on ATRA-induced proliferation of A spermatogonia was examined. The labeling index of A spermatogonia, 24 h after the administration of 0.25 mg ATRA, was significantly lowered by liarozole due to a shift of the maximal 5-bromo-deoxyuridine incorporation to an earlier point (20 h). This indicates that liarozole delays retinoid metabolism, thereby increasing the actual ATRA concentration, and more importantly, that ATRA by itself is an active retinoid in spermatogenesis. Apparently, ATRA does not need to be metabolized to 4-oxo-RA, which was previously shown to be a more potent inducer of spermatogonial proliferation than ATRA, to be effective.

Animals↗
PubMed1996

Retinoid X receptor-specific retinoids inhibit the ability of retinoic acid receptor-specific retinoids to increase the level of insulin-like growth factor binding protein-3 in human ectocervical epithelial cells.

The hormones derived from vitamin A and related synthetic ligands (retinoids) are important regulators of differentiation and development and have been shown to be therapeutically useful in the treatment of cervical cancer. All-trans-retinoic acid exerts its effects by activation of retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterodimers. These heterodimers bind to the retinoic acid response elements of target genes to regulate gene expression. RXR ligands act through RXR homodimers to regulate gene expression. In the present study, we describe the effects of RAR- and RXR-specific ligands on the regulation of insulin-like growth factor binding protein-3 (IGFBP-3) production and cell proliferation in human ectocervical epithelial (ECE) cell lines. Treatment of ECE16-1 cells with a RAR-specific ligand (TTNPB) or a ligand that interacts with both RAR and RXR receptors (9-cis-retinoic acid) increases IGFBP-3 levels and suppresses cell proliferation. In contrast, RXR-specific ligands (AGN191701, SR11217, and SR11237) do not regulate proliferation and slightly suppress the IGFBP-3 level. Cotreatment with increasing concentrations (0.01-1000nm) of RXR-specific ligand antagonizes the growth suppressive and IGFB-3-increasing effects of 1000 nM TTNPB. Similar results are observed in two other ECE cell lines, ECE16-D1 and ECE16-D2. These results indicate that RXR-specific ligands can antagonize RAR responses in these cell lines and suggest that a RAR-specific retinoid may be superior to one with mixed RAR/RXR binding activity for inhibiting cervical cancer cell proliferation. Moreover, the antagonism of RAR-dependent responses by RXR-specific ligands is consistent with a squelching model in which the RXR-specific ligand drives formation of RXR/RXR homodimers at the expense of the more active RAR/RXR heterodimers.

Cell Division↗
PubMed2002

Retinoid signaling is attenuated by proteasome-mediated degradation of retinoid receptors in human keratinocyte HaCaT cells.

The biological actions of retinoids are mediated by nuclear retinoid receptors, RAR and RXR, which are ligand-activated transcription factors. We investigated the mechanism of attenuation of retinoid receptor activity in human keratinocyte HaCaT cells. Treatment of HaCaT cells with all-trans-retinoic acid or 9-cis-retinoic acid reduced RARgamma and RXRalpha protein levels by one-half within 24 h. In contrast, retinoid treatment did not alter RARgamma or RXRalpha mRNA levels, suggesting that retinoids stimulate breakdown of their receptors. Pulse-chase studies revealed that retinoid treatment of HaCaT cells reduced RARgamma and RXRalpha half-lives by 50%, indicating that retinoids accelerate breakdown of their receptors. The proteasome inhibitor MG132 prevented retinoid-induced receptor loss. Furthermore, MG132 potentiated retinoid-induced receptor activity, as assessed by expression of the retinoid-regulated CRABP-II gene in HaCaT cells. These data demonstrate that retinoids attenuate retinoid receptor function by enhancing proteasome-mediated retinoid receptor breakdown in HaCaT cells. Proteasome-mediated degradation of RARgamma or RXRalpha in vitro was significantly reduced by the corepressor SMRT, which binds unliganded retinoid receptors. This protection from degradation was markedly diminished by ligand, which causes SMRT to dissociate from receptors. Ligand failed to relieve protection from degradation by SMRT of a mutant form of RXRalpha that binds SMRT in the presence and absence of ligand. Addition of coactivators TIF1, TIF2, and RIP140 had no effect on degradation of RARgamma or RXRalpha. In summary, ligand binding to retinoid receptors promotes proteasome-mediated receptor degradation via dissociation of SMRT. Ligand-stimulated receptor degradation results in attenuation of retinoid signaling.

Adult↗
PubMed1997

Control of Drosophila retinoid and fatty acid binding glycoprotein expression by retinoids and retinoic acid: northern, western and immunocytochemical analyses.

In Drosophila, thorough retinoid deprivation is possible, optimizing investigation of the effects of vitamin A metabolites and retinoic acid on the visual system. Retinoids had been found to control transcription and translation of Drosophila's opsin gene. To follow this line of inquiry, we examined the effect of retinoids on the translation and transcription of a Drosophila Retinoid and Fatty Acid Binding Glycoprotein. Western blots showed that this protein is high in retinoid replete flies and low in deprived flies. Flies grown on media capable of activating the opsin gene's transcription and which contain alternate transcription activators including retinoic acid yielded extracts containing significant amounts of Retinoid and Fatty Acid Binding Glycoprotein. Immunocytochemistry confirmed its absence in deprived flies and its presence in flies reared or replaced on these diverse media containing retinoids or general nutrients. Immunocytochemistry localized Retinoid and Fatty Acid Binding Glycoprotein to the Semper (cone) cells and the intraommatidial matrix (the interphotoreceptor matrix of the ommatidium). Positive staining of Semper cells in mutants of the opsin gene and a mutant lacking receptors suggests that Retinoid and Fatty Acid Binding Glycoprotein does not depend on presence of opsin and that it is not synthesized in receptor cells respectively. Northern blots demonstrated greatly diminished mRNA for Retinoid and Fatty Acid Binding Glycoprotein in flies grown on deprivation food relative to flies grown on normal food. Although the synthesis of Retinoid and Fatty Acid Binding Glycoprotein does not require chromophore precursors as does that of opsin, the control of Retinoid and Fatty Acid Binding Glycoprotein and opsin transcription by retinoids including retinoic acid might very well be the same. Our results suggest that Retinoid and Fatty Acid Binding Glycoprotein may be involved in retinoid transport. Also, Semper cells may be analogous to vertebrate retinal pigment epithelium in retinoid metabolism and/or delivery.

Animals↗
PubMed1997

Differential effects of synthetic nuclear retinoid receptor-selective retinoids on the growth of human non-small cell lung carcinoma cells.

Retinoids are promising agents for cancer chemoprevention and therapy. Nuclear retinoic acid receptors (RARs; RARalpha, -beta, and -gamma) and retinoid X receptors (RXRs; RXRalpha, -beta, and -gamma) are thought to mediate most of retinoids' effects on cell growth and differentiation. Because the majority of human non-small cell lung carcinoma (NSCLC) cell lines are resistant to all-trans-retinoic acid, we searched for more potent retinoids. Therefore, we examined the effects of 37 natural and synthetic retinoids that exhibit specific binding to and transactivation of individual RARs or RXRs on the proliferation of eight human NSCLC cell lines. All of these cells expressed mRNAs of the three RXRs; however, they expressed varying levels of RARalpha and RARgamma, and only three of the eight cell lines expressed RARbeta mRNA. Cellular retinoic acid-binding proteins (CRABPs) I and II were detected in one and three of the eight cell lines, respectively. Only 8 of the 37 retinoids exhibited growth-inhibitory activity (IC50, < 10 microM) against at least two of the eight NSCLC cell lines. The active retinoids included one (TD550) of five RARalpha-selective, one (Ch55) of three RARbeta-selective, three (CD437, CD2325, and SR11364) of six RARgamma-selective, and one (CD271) of four RARbeta/gamma-selective retinoids. The potency of these retinoids was low (IC50, > 1 microM), except for CD437, which was very potent (IC50, 0.1-0.5 microM). The six RXR-selective retinoids were mostly inactive even at 10 microM. However, combinations of RAR-selective and RXR-selective retinoids exhibited additive effects. There appeared to be no simple correlation among the histological type of the NSCLC (adeno- or squamous), the levels of nuclear receptors or CRABPs, and the response of the cells to the growth-inhibitory effects of retinoids. Nevertheless, in contrast with former studies with natural retinoids, these results suggest that several synthetic retinoids do exhibit inhibitory activity against NSCLC cells, and some of them may be useful clinically.

Antineoplastic Agents↗
PubMed1999

Interactions of retinoid binding proteins and enzymes in retinoid metabolism.

Naturally occurring retinoids (vitamin A or retinol and its active metabolites) are vital for vision, controlling the differentiation program of epithelial cells in the digestive tract and respiratory system, skin, bone, the nervous system, the immune system, and for hematopoiesis. Retinoids are essential for growth, reproduction (conception and embryonic development), and resistance to and recovery from infection. The functions of retinoids in the embryo begin soon after conception and continue throughout the lifespan of all vertebrates. Both naturally occurring and synthetic retinoids are used in the therapy of various skin diseases, especially acne, for augmenting the treatment of diabetes, and as cancer chemopreventive agents. Retinol metabolites serve as ligands that activate specific transcription factors in the superfamily of steroid/retinoid/thyroid/vitamin D/orphan receptors and thereby control gene expression. Additionally, retinoids may also function through non-genomic actions. Various retinoid binding proteins serve as partners in retinoid function. These binding proteins show high specificity and affinity for specific retinoids and seem to control retinoid metabolism in vivo qualitatively and quantitatively by reducing 'free' retinoid concentrations, protecting retinoids from non-specific interactions, and chaperoning access of metabolic enzymes to retinoids. Implementation of the physiological effects of retinoids depends on the spatial-temporal expressions of binding proteins, receptors and metabolic enzymes. This review will discuss current understanding of the enzymes that catalyze retinol and retinoic acid metabolism and their unique and integral relationship to retinoid binding proteins.

Alcohol Dehydrogenase↗
PubMed2000

Retinoid-binding proteins: mediators of retinoid action.

Active vitamin A metabolites, known as retinoids, are essential for multiple physiological processes, ranging from vision to embryonic development. These small hydrophobic compounds associate in vivo with soluble proteins that are present in a variety of cells and in particular extracellular compartments, and which bind different types of retinoids with high selectivity and affinity. Traditionally, retinoid-binding proteins were viewed as transport proteins that act by solubilizing and protecting their labile ligands in aqueous spaces. It is becoming increasingly clear, however, that, in addition to this general role, retinoid-binding proteins have diverse and specific functions in regulating the disposition, metabolism and activities of retinoids. Some retinoid-binding proteins appear to act by sequestering their ligands, thereby generating concentration gradients that allow cells to take up retinoids from extracellular pools and metabolic steps to proceed in energetically unfavourable directions. Other retinoid-binding proteins regulate the metabolic fates of their ligands by protecting them from some enzymes while allowing metabolism by others. In these cases, delivery of a bound retinoid from the binding protein to the 'correct' enzyme is likely to be mediated by direct and specific interactions between the two proteins. One retinoid-binding protein was reported to enhance the ability of its ligand to regulate gene transcription by directly delivering this retinoid to the transcription factor that is activated by it. 'Channelling' of retinoids between their corresponding binding protein and a particular protein target thus seems to be a general theme through which some retinoid-binding proteins exert their effects.

Animals↗
PubMed2003

Growth inhibitory retinoid effects after recruitment of retinoid X receptor beta to the retinoic acid receptor beta promoter.

Nuclear retinoid receptors mediate retinoid effects through tissue-specific, ligand-receptor interactions and subsequent transcriptional regulation of secondary target genes. Retinoic acid receptor beta (RARbeta) is itself a retinoid target gene with a retinoic acid response element (betaRARE) in the 5' untranslated region of the RARbeta2 gene. Altered transcriptional regulation of RARbeta may play a role in human carcinogenesis and the retinoid-responsiveness of malignant cells. Here we used retinoid X receptor-specific antibodies in electrophoretic mobility shift assays to show that the retinoid X receptor beta (RXRbeta) protein was recruited to the betaRARE, after retinoid treatment of retinoid-sensitive neuroblastoma (NB), lung and breast cancer cell lines, but not retinoid-resistant lung and breast cancer cell lines. RXRbeta selectively enhanced retinoid-induced transcriptional activation of the betaRARE. Stable overexpression of RXRalpha and RXRbeta in NB cells resulted in marked growth inhibition and cell death, which increased after retinoid treatment. However, only proteins from the RXRbeta transfectants exhibited specific RXRbeta binding to the betaRARE in vitro and in vivo, enhanced histone acetylation and increased endogenous RARbeta expression. These data indicate that recruitment of RXRbeta to the betaRARE, and consequent induction of endogenous RARbeta expression, is an important component in the retinoid anticancer signal. RXRalpha may also participate in the retinoid signal, but through mechanisms that do not involve RARbeta.

Acetylation↗
PubMed1997

Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids.

All-trans-retinoic acid (trans-RA) and other retinoids exert anticancer effects through two types of retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs). Previous studies demonstrated that the growth-inhibitory effects of trans-RA and related retinoids are impaired in certain estrogen-independent breast cancer cell lines due to their lower levels of RAR alpha and RARbeta. In this study, we evaluated several synthetic retinoids for their ability to induce growth inhibition and apoptosis in both trans-RA-sensitive and trans-RA-resistant breast cancer cell lines. Our results demonstrate that RXR-selective retinoids, particularly in combination with RAR-selective retinoids, could significantly induce RARbeta and inhibit the growth and induce the apoptosis of trans-RA-resistant, RAR alpha-deficient MDA-MB-231 cells but had low activity against trans-RA-sensitive ZR-75-1 cells that express high levels of RAR alpha. Using gel retardation and transient transfection assays, we found that the effects of RXR-selective retinoids on MDA-MB-231 cells were most likely mediated by RXR-nur77 heterodimers that bound to the RA response element in the RARbeta promoter and activated the RARbeta promoter in response to RXR-selective retinoids. In contrast, growth inhibition by RAR-selective retinoids in trans-RA-sensitive, RAR alpha-expressing cells most probably occurred through RXR-RAR alpha heterodimers that also bound to and activated the RARbeta promoter. In MDA-MB-231 clones stably expressing RAR alpha, both RARbeta induction and growth inhibition by RXR-selective retinoids were suppressed, while the effects of RAR-selective retinoids were enhanced. Together, our results demonstrate that activation of RXR can inhibit the growth of trans-RA-resistant MDA-MB-231 breast cancer cells and suggest that low cellular RAR alpha may regulate the signaling switch from RAR-mediated to RXR-mediated growth inhibition in breast cancer cells.

Antineoplastic Agents↗
PubMed1995

Correlation of retinoid binding affinity to retinoic acid receptor alpha with retinoid inhibition of growth of estrogen receptor-positive MCF-7 mammary carcinoma cells.

Both anchorage-dependent growth and anchorage-independent growth of the estrogen receptor-positive mammary carcinoma cell line MCF-7 are inhibited by all-trans-retinoic acid. This cell line has nuclear retinoic acid receptors (RARs) alpha and gamma. The natural retinoids all-trans-retinoic acid and 9-cis-retinoic acid and a series of 12 conformationally restricted retinoids, which showed a range of binding selectivities for these receptors and had either agonist or antagonist activity for gene transcriptional activation by the RARs, were evaluated for their abilities to inhibit anchorage-dependent (adherent) and anchorage-independent (clonal) growth of MCF-7 cells. Correlation analyses were performed to relate growth inhibition by these retinoids with their binding affinity to RAR alpha or RAR gamma. Inhibition of anchorage-dependent growth in culture after 7 days of retinoid treatment correlated with binding to RAR alpha (n = 14; P < or = 0.001) and not to RAR gamma (n = 14; P > 0.1). Both the RAR alpha-selective retinoid agonists and the two RAR antagonists that were evaluated inhibited adherent cell growth. The RAR gamma-selective agonists had very low growth inhibitory activity (< 10%) at concentrations as high as 12.5 microM. These results suggest that RAR alpha is the retinoid receptor involved in the inhibition of adherent cell growth by retinoids and that transcriptional activation by this receptor on a RAR response element does not appear to be required for this process to occur. For this series of retinoids, inhibition of anchorage-independent growth after 21 days of retinoid treatment only correlated (n = 12; P < or = 0.005) with binding affinity to RAR alpha for the retinoid agonists, although the RAR gamma-selective retinoids displayed weak activity. The RAR antagonists were very poor inhibitors of growth. These results suggest that activation of gene transcription by RAR alpha appears to be required for inhibition of anchorage-independent growth by retinoids in this estrogen receptor-positive mammary carcinoma cell line.

Animals↗
PubMed1996

Differential regulation of human ectocervical epithelial cell line proliferation and differentiation by retinoid X receptor- and retinoic acid receptor-specific retinoids.

Retinoids are important regulators of human papillomavirus (HPV)-immortalized cervical epithelial cell differentiation and have been successfully used in the treatment of HPV-involved cervical cancer. In the present study, we examine the effects of a series of natural and synthetic retinoids on differentiation and proliferation of HPV-16-positive lines, ECE16-1 and CaSki. Retinoic acid receptor alpha (RAR alpha), RAR gamma, and retinoid X receptor alpha (RXR alpha) are the major retinoid receptor subtypes expressed when ECE16-1 cells are grown in retinoid-free medium. Our results indicate that ligands that interact with RARs only or both RARs and RXRs, including all-trans-retinoic acid (all-trans-RA), 9-cis-retinoic acid (9-cis-RA), 13-cis-retinoic acid (13-cis-RA), and several synthetic retinoids, suppress ECE16-1 cell proliferation, regulate expression of the retinoid-responsive differentiation marker cytokeratin K5, and increase RAR beta mRNA levels. In contrast, ligands that specifically interact with RXRs do not suppress proliferation and are less efficient regulators of gene expression. CaSki cells express greatly reduced RAR and RXR levels compared to ECE16-1 cells. However, both RAR- and RXR-specific ligands increase CaSki number by > or = 20%. In addition, RXR-specific ligands suppress cytokeratin K5 mRNA levels slightly, compared to RAR-specific ligands that strongly suppress K5 mRNA levels. We also compare the effects of these agents on the proliferation of other cervical cell lines, including ECE16-D2, ME180, and SiHa cells. ECE16-D2 and ME180 cells are growth suppressed by RAR-specific, but not RXR-specific, retinoids. SiHa cells are not responsive to either class of retinoid. Our results indicate that: (a) the response of different human cervical cell lines varies following treatment with receptor type-specific retinoids; and (b) the relationship between retinoid regulation of proliferation and differentiation can be uncoupled.

Cell Differentiation↗
PubMed1996

Retinoic acid receptor- and retinoid X receptor-selective retinoids activate signaling pathways that converge on AP-1 and inhibit squamous differentiation in human bronchial epithelial cells.

Human bronchial epithelial (HBE) cells undergo squamous differentiation in response to a variety of conditions in tissue culture, and retinoid treatment has been shown to reverse this process. Retinoids mediate their effects through the retinoic acid and retinoid X nuclear receptors (RAR and RXR, respectively), which form RAR-RXR heterodimers, RXR homodimers, and heterodimers of RXR and certain orphan receptors. These receptor dimers bind to distinct response elements, activating separate pathways. In this study, we investigated the roles of RAR and RXR signaling pathways in the inhibition of HBE squamous differentiation. After induction of squamous differentiation by confluent growth, HBE cells were treated with retinoids that selectively activate RARs (E-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaienyl)-1- propenyl] benzoic acid), RXRs (4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid), or both RARs and RXRs (9-c/s retinoic acid). These retinoids inhibited the mRNA expression of the squamous differentiation markers transglutaminase type I, involucrin, keratin 5, and keratin 13, suggesting that inhibition of HBE squamous differentiation could be mediated by activation of either RAR or RXR signaling pathways. We examined the role of AP-1 as a potential effector of these retinoid pathways. AP-1 transcriptional activity was reduced markedly by these retinoids, and a concomitant, but proportionally smaller, reduction in AP-1 DNA binding was observed. Furthermore, treatment of squamous HBE cells with the retinoid SR11238, which inhibited AP-1 without activating retinoid receptor transcriptional properties, reduced the expression of transglutaminase type I and involucrin. These findings support the hypothesis that, in HBE cells, RAR and RXR signaling pathways inhibit AP-1 transcriptional activity, and this contributes to retinoid-induced reversal of HBE squamous differentiation.

Alitretinoin↗
PubMed1988

Distributions of retinoids, retinoid-binding proteins and related parameters in different types of liver cells isolated from young and old rats.

The levels of retinoids, retinol-binding protein, cellular retinol-binding protein, cellular retinoic-acid-binding protein, transthyretin and the activities of retinyl palmitate hydrolase and cholesteryl oleate hydrolase were determined in purified parenchymal, fat-storing, endothelial and Kupffer cell preparations, and in liver homogenates from young adult (6-month-old) and old (36-month-old) rats. Retinoid levels were also determined in the plasma from young and old rats. Retinoid contents were determined by HPLC. The binding proteins and transthyretin were measured by specific radioimmunoassays; retinyl palmitate and cholesterol oleate hydrolases were measured by sensitive microassays. The retinoid content of both the liver homogenates and of the fat-storing, and parenchymal cell preparations increased between 6 months and 36 months of age. The cellular distribution of retinoids was similar for the two age groups analyzed with the fat-storing cells being the main retinoid storage sites in the rat liver. Concentrations of retinol-binding protein and transthyretin were high in parenchymal cell preparations. Cellular retinol-binding protein was enriched both in parenchymal and in fat-storing cell preparations; the highest concentrations of cellular retinoic-acid-binding protein were present in fat-storing cell preparations. No major differences were observed between the two age groups in the cellular concentrations and distributions of any of these binding proteins. High activity of cholesterol oleate hydrolase was measured in parenchymal and in Kupffer cell preparations; endothelial cell preparations also contained considerable activities. The distribution of this activity over the various cell types reflects their role in lipoprotein metabolism. Retinyl palmitate hydrolase activity was specifically enriched in parenchymal and in fat-storing cell preparations, consistent with the roles of these cells in retinoid metabolism. No major differences were observed between the two age groups in the cellular distributions of the two hydrolase activities. This study indicates that no major changes occur in the retinoid-related parameters analyzed with age, suggesting that rat liver retinoid metabolism does not change dramatically with age and that retinoid homeostasis is maintained.

Aging↗