All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo

Zirn, Birgit; Samans, Birgit; Spangenberg, Christian; Graf, Norbert; Eilers, Martin; Gessler, Manfred

doi:10.1038/sj.onc.1208725

Cited by 43 publications

(50 citation statements)

References 32 publications

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“…However, some of the genes not regulated in MEFs are RA regulated in other cell types or tissues. For example, Gde1 is RA regulated in Wilms' tumor cells (64), while Myc is regulated in various cell types but not in MEFs (4). It remains to be determined whether all RARbound genes can be RA regulated in the appropriate cell type and under the appropriate conditions or whether there are instances in which RAR is always a silent partner.…”

Section: Discussionmentioning

confidence: 99%

Cell-Specific Interaction of Retinoic Acid Receptors with Target Genes in Mouse Embryonic Fibroblasts and Embryonic Stem Cells

Delacroix

Moutier

Altobelli

et al. 2010

Molecular and Cellular Biology

151

139

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All-trans retinoic acid (RA) induces transforming growth factor beta (TGF-␤)-dependent autocrine growth of mouse embryonic fibroblasts (MEFs). We have used chromatin immunoprecipitation to map 354 RA receptor (RAR) binding loci in MEFs, most of which were similarly occupied by the RAR␣ and RAR␥ receptors. Only a subset of the genes associated with these loci are regulated by RA, among which are several critical components of the TGF-␤ pathway. We also show RAR binding to a novel series of target genes involved in cell cycle regulation, transformation, and metastasis, suggesting new pathways by which RA may regulate proliferation and cancer. Few of the RAR binding loci contained consensus direct-repeat (DR)-type elements. The majority comprised either degenerate DRs or no identifiable DRs but anomalously spaced half sites. Furthermore, we identify 462 RAR target loci in embryonic stem (ES) cells and show that their occupancy is cell type specific. Our results also show that differences in the chromatin landscape regulate the accessibility of a subset of more than 700 identified loci to RARs, thus modulating the repertoire of target genes that can be regulated and the biological effects of RA.

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Section: Discussionmentioning

confidence: 99%

Cell-Specific Interaction of Retinoic Acid Receptors with Target Genes in Mouse Embryonic Fibroblasts and Embryonic Stem Cells

Delacroix

Moutier

Altobelli

et al. 2010

Molecular and Cellular Biology

151

139

View full text Add to dashboard Cite

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“…Activation of peroxisome proliferator-activated receptor γ (PPARγ), which inhibits the growth of breast and prostate cancer cells as well as metastasis of lung tumor cells, was shown to increase expression of DLC1 in association with inhibition of the invasiveness of lung cancer cells that overexpress PPARγ [9]. All-trans retinoic acid inhibits the proliferation of normal cells as well as that of various types of tumor cells, and culture of Wilms' tumor cells with alltrans-retinoic acid induced expression of DLC1 [10]. Comprehensive gene expression profiling also revealed that doxorubicin, the most widely used drug for treatment of breast cancer, increased the expression of genes important in apoptosis, cell proliferation, cell cycle checkpoints, and suppression of metastasis, including that of DLC1, in breast cancer patients [11].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

Ullmannova

Popescu

2007

Cancer Detection and Prevention

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Background-Dietary flavone was previously shown to increase the expression of deleted in liver cancer-1 gene (DLC-1) in HT-29 colon carcinoma cell line (Proteomics 2004;4:2455-64). DLC-1 that encodes a Rho GTPase-activating protein, functions as a tumor suppressor gene and is frequently inactivated or down-regulated in several common cancers. Restoration of DLC-1 expression suppresses in vitro tumor cells proliferation and tumorigenicity in vivo.Methods-Here, the effect of flavone was examined in several DLC-1-deficient cell lines derived from different types human cancer using assays for cell proliferation, gene expression and transfer.Results-We show that exposure to 15μM flavone increased DLC1 expression in breast but not in liver or prostate carcinoma cells or a nonmalignant breast epithelial cell line. Flavone restored the expression of DLC1 in the breast carcinoma cell lines MDA-MB-468, MDA-MB-361, and BT20 as well as in the colon carcinoma cell line HT-29 all of which are DLC-1-negative due to promoter hypermethylation. We further show that flavone inhibited cell proliferation, induced cell cycle arrest at G2-M, increased p21 Waf1 gene expression, and caused apoptosis. Microarray analysis of these aggressive and metastatic breast carcinoma cells revealed 29 flavone-responsive genes, among which the DNA damage-inducible GADD genes were up-regulated and the proto-oncogene STMN1 and IGFBP3 were down-regulated.Conclusions-Flavone-mediated alterations of genes that regulate tumor cell proliferation, cell cycle, and apoptosis contribute to chemopreventive and antitumoral effects of flavone. Alone or in combination with demethylating agents, flavone may be an effective adjunct to chemotherapy in preventing breast cancer metastasis.

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“…The addition of the pan-retinoic acid receptor inverse agonist (BMS493) attenuated the ability of Tazarotene to enhance the angiogenesis. In contrast, the incubation of Tazarotene with an RXR antagonist (UVI3003) 22 did not affect the proangiogenic phenotype of Tazarotene (Figure 3b). These data clearly indicate that the effect of Tazarotene on the branching tubule remodeling is only mediated through RAR binding.…”

Section: Tazarotene Promotes Angiogenesis Via Retinoic Acid Receptor mentioning

confidence: 81%

“…Intraperitoneal administration of Tazarotene was well tolerated (see Supplementary Figure S6) and resulted in enhanced expression of hepatic RARRES1 (a retinoid pathway target 22 ) indicating that Tazarotene was systemically bioactive (see Supplementary Figure S7). The invasion and the growth of microvessels into the Matrigel implant was quantified by CD31 and α-smooth muscle (SM) actin staining of endothelium and mural cells, and was significantly higher following systemic Tazarotene.…”

Section: Tazarotene Stimulates In Vivo Functional Neovascularizationmentioning

confidence: 99%

The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing

et al. 2016

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Therapeutic angiogenesis is a major goal of regenerative medicine, but no clinically approved small molecule exists that enhances new blood vessel formation. Here we show, using a phenotype-driven high-content imaging screen of an annotated chemical library of 1,280 bioactive small molecules, that the retinoid agonist Tazarotene, enhances in vitro angiogenesis, promoting branching morphogenesis, and tubule remodeling. The proangiogenic phenotype is mediated by retinoic acid receptor but not retinoic X receptor activation, and is characterized by secretion of the proangiogenic factors hepatocyte growth factor, vascular endothelial growth factor, plasminogen activator, urokinase and placental growth factor, and reduced secretion of the antiangiogenic factor pentraxin-3 from adjacent fibroblasts. In vivo, Tazarotene enhanced the growth of mature and functional microvessels in Matrigel implants and wound healing models, and increased blood flow. Notably, in ear punch wound healing model, Tazarotene promoted tissue repair characterized by rapid ear punch closure with normal-appearing skin containing new hair follicles, and maturing collagen fibers. Our study suggests that Tazarotene, an FDA-approved small molecule, could be potentially exploited for therapeutic applications in neovascularization and wound healing.

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All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo

Cited by 43 publications

References 32 publications

Cell-Specific Interaction of Retinoic Acid Receptors with Target Genes in Mouse Embryonic Fibroblasts and Embryonic Stem Cells

Cell-Specific Interaction of Retinoic Acid Receptors with Target Genes in Mouse Embryonic Fibroblasts and Embryonic Stem Cells

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing

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