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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoic acid (RA) is required for normal airway epithelial cell growth and differentiation both in vivo and in vitro. One of the earliest events following the exposure of bronchial epithelial cells to RA is the strong induction of RA receptor beta (RAR beta) mRNA. Previous work established that many lung cancer cell lines and primary tumors display abnormal RAR beta mRNA expression, most often absence or weak expression of the RAR beta 2 isoform, even after RA treatment. Restoration of RAR beta 2 into RAR beta-negative lung cancer cell lines has been reported to inhibit tumorigenicity. Since RAR beta 2 inactivation may contribute to lung cancer, we have investigated the molecular mechanism of defective RAR beta 2 expression. Nuclear run-on assays and transient transfections with RAR beta 2 promoter constructs indicate the presence of trans-acting transcriptional defects in most lung cancer cell lines, which map to the RA response element (RARE). These defects cannot be complemented by RAR-retinoid X receptor cotransfection and can be separated into two types: (i) one affecting transcription from direct repeat RAREs, but not palindromic RAREs, and (ii) another affecting transcription from both types of RARE. Studies using chimeras between RAR alpha, TR alpha, and other transcription factors suggest the existence of novel RAR-thyroid hormone receptor AF-2-specific cofactors, which are necessary for high levels of transcription. Furthermore, these factors may be frequently inactivated in human lung cancer.
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PMID:Evidence for impaired retinoic acid receptor-thyroid hormone receptor AF-2 cofactor activity in human lung cancer. 779

Retinoic acid (RA) and nuclear retinoic acid receptors (RARs) have been implicated in a variety of human malignancies including lung cancer, and RA has been proposed as a chemopreventive agent for bronchogenic carcinoma. Normal human tracheobronchial epithelial cells show dramatic induction of RAR-beta mRNA and significant growth inhibition after RA treatment. In contrast, 17 of 22 small cell lung cancer (SCLC) and 9 of 15 non-SCLC lines treated with 1 microM RA showed no significant growth inhibition. Of interest, 5 SCLC lines with high levels of myc gene family expression related to c-, N-, or L-myc gene amplification exhibited growth inhibition (28-87%), whereas 2 non-SCLC lines actually showed growth stimulation after treatment with 1 microM RA. The lines varied greatly in their constitutive expression of RAR-beta mRNA, and 15 of 20 SCLC and 8 of 15 non-SCLC lines failed to show RAR-beta mRNA induction after RA treatment. Six cell lines showed possible alterations in the coding region of RAR-beta by complementary DNA (cDNA)/polymerase chain reaction (PCR) analysis using primers common to the RAR-beta1,2,3 isoforms, since other regions would undergo cDNA/PCR amplification whereas the DNA binding domain would not. Nonetheless, no abnormal band shift patterns in cDNA amplified by PCR were found by single strand conformation polymorphism analysis covering all 1344 base pairs of the RAR-beta open reading frame. Finally, no abnormalities in RAR-alpha gene structure or expression were identified by Southern and Northern blot analysis, including lines with cytogenetic abnormalities of 17q21. We conclude that abnormalities of the RAR-beta system are common in human lung cancer cell lines.
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PMID:Human lung cancer cell lines exhibit resistance to retinoic acid treatment. 827 49

Retinoic acid has been shown to be an anticancer agent, and a growing literature suggests that it is the nuclear retinoic acid receptor beta2 (RARbeta2) that is primarily responsible for mediating this effect, at least in some systems. To determine whether partial inactivation of RARbeta2 would predispose to lung cancer in mice, we generated three transgenic lines expressing antisense sequences. When killed at 13-3/4-18 months of age, 21/36 animals had a total of 43 pulmonary tumors superficially visible upon necropsy, whereas among 23 nontransgenic mice, only 1 had a single visible lung tumor. A twofold higher incidence of lung tumors was seen in homozygous vs. hemizygous antisense mice. The endogenous RARbeta2 message level was reduced in transgenic lung tissue and further reduced in the tumors. RARbeta4, a truncated isoform derived from the same transcript as RARbeta2, does not carry the sequence identified by the antisense construct and its message was not as strongly affected. Immunofluorescence studies showed that RARbeta was virtually undetectable in the tumors, but present in normal tissue. We conclude that RARbeta2, but probably not RARbeta4, plays an important role in suppression of murine lung tumorigenesis.
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PMID:Lung tumors in mice expressing an antisense RARbeta2 transgene. 880 Nov 72

Vitamin A analogs (retinoids) suppress oral and lung carcinogenesis in animal models and prevent the development of second primary tumors in head, neck, and lung cancer patients. These effects result from changes in the expression of genes that regulate cell growth and differentiation. Retinoic acid receptors (RARs; -alpha, -beta, and -gamma) and retinoid X receptors (RXRs; -alpha, -beta, and, -gamma) are retinoid-activated transcription factors, which mediate effects of retinoids on gene expression. Therefore, alterations in receptor expression or function could interfere with the retinoid signaling pathway and thereby enhance cancer development. We found that the expression of RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer and in dysplastic lesions adjacent to cancer and in malignant oral and lung carcinomas. The expression of the other receptors was not different among normal, dysplastic, and malignant oral tissues. However, the expression of RAR gamma and RXR beta was somewhat decreased in lung cancers. These results show that RAR beta expression is lost at early stages of carcinogenesis in the aerodigestive tract and support the hypothesis that the loss of RAR beta expression may facilitate the development of some of these cancers.
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PMID:Roles of retinoids and their nuclear receptors in the development and prevention of upper aerodigestive tract cancers. 925 92

Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.
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PMID:Retinoic acid prevents experimental Cushing syndrome. 1160 19

Cyclooxygenase-2 (COX-2) is frequently expressed in cancer cells, contributing to tumor development. Most studies of COX-2 expression have examined artificially induced expression in noncancer cells rather than basal expression in cancer cells. Therefore, basal COX-2 expression and its regulation were examined in cell lines derived from a murine model of lung adenocarcinoma. The presence of COX-2 protein in these cells was demonstrated by Western analysis. COX-2 promoter activity was repressed by U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene], a mitogen-activated protein kinase kinase inhibitor, as well as SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole], an inhibitor of p38 mitogen-activated protein kinase, substantiating the involvement of these signal transduction pathways in the regulation of basal COX-2 expression. Retinoic acid also repressed promoter activity, yet increased activity significantly in one cell line after 18 and 30 h of treatment. Deletions of the murine COX-2 promoter revealed that the 5' transcription factor binding sites were not required for basal expression, including the only nuclear factor-kappaB sites of the promoter. Site-directed mutagenesis of the 3' C/EBP (CCAAT/enhancer-binding protein) sites inhibited promoter activity by 20 to 55%, while mutation of the 3' ATF/CREB/AP-1 (activating transcription factor/cAMP response element-binding protein/activator protein-1) site inhibited activity by 70%. Mutation of the 3' upstream stimulatory factor site did not affect promoter activity. Electrophoretic mobility shift assays indicated that the AP-1 transcription factor does not bind to the 3' ATF/CREB/AP-1 site, leaving C/EBP and ATF/CREB as the major transcriptional regulators of basal expression of COX-2 in these lung tumor-derived cell lines and identifying new targets for the prevention/treatment of lung cancer through the modulation of COX-2 expression.
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PMID:Transcriptional regulation of basal cyclooxygenase-2 expression in murine lung tumor-derived cell lines by CCAAT/enhancer-binding protein and activating transcription factor/cAMP response element-binding protein. 1213 Jun 85

Retinoic acid (RA) and sodium butyrate (NaB) have been implicated in the regulation of growth and differentiation in various cancer cells. To produce an agent with the properties of both RA and NaB, a butyryl aminophenyl ester of RA (4-BPRE) was synthesized. The agent was compared with an aminophenyl ester devoid of the butyryl group (4-APRE) for antitumor potential in vitro. Like RA, 4-hydroxyphenyl retinamide (4-HPR) and 4-APRE, 4-BPRE was an active ligand for all three subtypes of RAR, but not for RXR, as determined by transcription assays in COS-1 cells. In addition, regardless of the butyryl group, 4-BPRE actively suppressed c-Jun transcriptional activity, which may result in reduced expression of matrix metalloproteinases (MMP-1 and MMP-2), and effectively inhibited HCT116 cell invasion into Matrigel. In these respects, 4-BPRE is similar to 4-APRE, and even to RA and 4-HPR. However, our results showed that in HCT116 colon and A549 lung cancer cells, 4-BPRE was much more cytotoxic than RA and 4-APRE, and was also more cytotoxic than 4-HPR, which is the most cytotoxic retinoid derivative under clinical investigation. Subsequent assays using DAPI staining, DNA fragmentation, and FACS analysis suggested that the cytotoxic effect of 4-BPRE is mediated by apoptosis in HCT116 cells. Moreover, 4-BPRE inhibited histone deacetylase (HDAC) activity to some degree, although inhibition was less than that induced by the known HDAC inhibitors TSA and NaB. These results suggest that 4-BPRE could be a promising antitumor retinoid with both NaB activity and RA function.
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PMID:In vitro antitumor potential of 4-BPRE, a butyryl aminophenyl ester of retinoic acid: role of the butyryl group. 1476 28

Retinoic acid (RA) is the ligand for nuclear RA receptors (RARs and RXRs) and is crucial for normal epithelial cell growth and differentiation. During malignant transformation, human bronchial epithelial cells acquire a block in retinoid signaling caused in part by a transcriptional defect in RARs. Here, we show that activation of c-Jun N-terminal kinase (JNK) contributes to RAR dysfunction by phosphorylating RARalpha and inducing degradation through the ubiquitin-proteasomal pathway. Analysis of RARalpha mutants and phosphopeptide mapping revealed that RARalpha residues Thr181, Ser445, and Ser461 are phosphorylated by JNK. Mutation of these residues to alanines prevented efficient ubiquitination of RARalpha and increased the stability of the protein. We investigated the importance of RARalpha phosphorylation by JNK as a mediator of retinoid resistance in lung cancer. Mice that develop lung cancer from activation of a latent K-ras oncogene had high intratumoral JNK activity and low RARalpha levels and were resistant to treatment with an RAR ligand. JNK inhibition in a human lung cancer cell line enhanced RARalpha levels, ligand-induced activity of RXR-RAR dimers, and growth inhibition by RA. These findings point to JNK as a key mediator of aberrant retinoid signaling in lung cancer cells.
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PMID:c-Jun N-terminal kinase contributes to aberrant retinoid signaling in lung cancer cells by phosphorylating and inducing proteasomal degradation of retinoic acid receptor alpha. 1565 32

Vitamin A is used as a generic term for all vitamin A derivatives with retinol-like biological activity. Retinol is the main parent compound for vitamin A. It derives from carotenoids (provitamin A) and also directly from the pre-formed vitamin A contained in the diet. The term "retinoid" is a generic descriptor of compounds structurally related to vitamin A and the synthetic analogues of retinol with or without biological activity. Retinoic acid is the active cellular catabolite. Vitamin A/retinoids have been given cancer-preventive functions and subsequently used in clinical trials to reduce lung cancer incidence in high-risk individuals. The results obtained have been in contradiction with both in vivo and in vitro promising studies. It seems therefore necessary to develop a better understanding of the vitamin A/retinoids signalling pathways in the lung. With this aim, we summarise the relevant knowledge focussed on the lung.
Lung Cancer 2009 Oct
PMID:Vitamin A/retinoids signalling in the human lung. 1934 27

Lung cancer is the second leading deadly cancer in United States. In 2007, the United States reported 213,380 new lung cancer diagnoses and 160,390 deaths caused by lung cancer. Retinoic acid and retinyl esters are the oxidized and storage forms of vitamin A in the body. At low levels, they maintain many functions as hormones affecting vision, bone growth, reproduction, cellular division, and differentiation. Recent publications have found retinoid receptors to be effective therapeutic targets in some cancer cell lines and that retinoids were functional cell modulators of the RAR/RXR nuclear hormone receptors that may impact the development of lung cancer. We hypothesize that retinoic acid and retinyl esters will negatively impact the A549 lung carcinoma cell line model in vitro and that exposure to higher concentrations of retinoids will induce impairments indicative of metabolic implications seen in chronic conditions such as cancer. Citrals are specific inhibitors of retinoid metabolism and are employed to ascertain the specificity of retinoid impacts on the cell model. The aim of this study was to expose the A549 cell line model to various concentrations of retinoic acid, and Citrals (0-160 g/ml). Growth patterns of exposed cells were screened during time intervals ranging from 24-72 hours. The effects were measured through phase microscopy, cell proliferation MTT assay, FACS analysis for cell cycle parameters and western blot analyses for cyclins. Data generated from phase contrast microscopy and MTT assays showed an increased physical destruction, metabolic impairment and a decrease in the viability of A549 cell line model after 72 hours of exposure to retinoic acids and. Observations on the effects exhibited with Citrals (cis and trans vs. diethyl acetal) suggests the reversal of retinoid toxicity and a decrease in cell metabolic as well as physical destructions and positive cell proliferation. Results from FACS analysis showed modulation in the cell cycle distribution/progression upon exposure to retinoids and that Citrals did reverse these effects in the cell line model. Western blot analysis confirmed the findings obtained from testing parameters. We conclude that modulation of metabolic integrity, cell cycle distribution and cell survival through retinoids/citrals in the lung carcinoma model is promising and warrants further therapeutic investigation.
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PMID:Retinoids and citral modulated cell viability, metabolic stability, cell cycle progression and distribution in the a549 lung carcinoma cell line - biomed 2010. 2046 16


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