Revealing a natural marine product as a novel agonist for retinoic acid receptors with a unique binding mode and inhibitory effects on cancer cells

2012 ◽  
Vol 446 (1) ◽  
pp. 79-87 ◽  
Author(s):  
Shanshan Wang ◽  
Zhao Wang ◽  
Shengchen Lin ◽  
Weili Zheng ◽  
Rui Wang ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cancer Cells ◽  
Target Genes ◽  
Functional Characterization ◽  
Acid Resistance ◽  
Binding Mode ◽  
Therapeutic Agents ◽  
Covalent Modification ◽  
Marine Product

Retinoids display anti-tumour activity on various cancer cells and therefore have been used as important therapeutic agents. However, adverse side effects and RA (retinoic acid) resistance limit further development and clinical application of retinoid-based therapeutic agents. We report in the present paper the identification of a natural marine product that activates RARs (RA receptors) with a chemical structure distinct from retinoids by high-throughput compound library screening. Luffariellolide was uncovered as a novel RAR agonist by inducing co-activator binding to these receptors in vitro, further inhibiting cell growth and regulating RAR target genes in various cancer cells. Structural and molecular studies unravelled a unique binding mode of this natural ligand to RARs with an unexpected covalent modification on the RAR. Functional characterization further revealed that luffariellolide displays chemotherapeutic potentials for overcoming RA resistance in colon cancer cells, suggesting that luffariellolide may represent a unique template for designing novel non-retinoid compounds with advantages over current RA drugs.

scholarly journals Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1977-1984 ◽  
Author(s):  
M Kizaki ◽  
MI Dawson ◽  
R Heyman ◽  
E Elster ◽  
R Morosetti ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Clonal Growth ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Synergistic Effects ◽  
Leukemic Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Differentiation And Proliferation ◽  
Acute Myeloid

The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL- 60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.

Constitutive Degradation of PML/RAR Through the Proteasome Pathway Mediates Retinoic Acid Resistance

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1477-1481 ◽  
Author(s):  
Mirco Fanelli ◽  
Saverio Minucci ◽  
Vania Gelmetti ◽  
Clara Nervi ◽  
Carlo Gambacorti-Passerini ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Proteasome Inhibitors ◽  
Acid Resistance ◽  
Parental Cell ◽  
Parental Cell Line ◽  
In Vitro Degradation ◽  
Nb4 Cells ◽  
Proteasome Pathway ◽  
Retinoic Acid Resistance

Abstract PML/RAR is the leukemogenetic protein of acute promyelocytic leukemia (APL). Treatment with retinoic acid (RA) induces degradation of PML/RAR, differentiation of leukaemic blasts, and disease remission. However, RA resistance arises during RA treatment of APL patients. To investigate the phenomenon of RA resistance in APL, we generated RA-resistant sublines from APL-derived NB4 cells. The NB4.007/6 RA-resistant subline does not express the PML/RAR protein, although its mRNA is detectable at levels comparable to those of the parental cell line. In vitro degradation assays showed that the half-life of PML/RAR is less than 30 minutes in NB4.007/6 and longer than 3 hours in NB4. Treatment of NB4.007/6 cells with the proteasome inhibitors LLnL and lactacystin partially restored PML/RAR protein expression and resulted in a partial release of the RA-resistant phenotype. Similarly, forced expression of PML/RAR, but not RAR, into the NB4/007.6 cells restored sensitivity to RA treatment to levels comparable to those of the NB4 cells. These results indicate that constitutive degradation of PML/RAR protein may lead to RA resistance and that PML/RAR expression is crucial to convey RA sensitivity to APL cells.

scholarly journals Physiological and Receptor-selective Retinoids Modulate Interferon γ Signaling by Increasing the Expression, Nuclear Localization, and Functional Activity of Interferon Regulatory Factor-1

2005 ◽  
Vol 280 (43) ◽  
pp. 36228-36236 ◽  
Author(s):  
Xin M. Luo ◽  
A. Catharine Ross
Keyword(s):  
Retinoic Acid ◽  
Nuclear Localization ◽  
Target Genes ◽  
Interferon Γ ◽  
Epithelial Cell Line ◽  
Transcriptional Level ◽  
Signal Transducer ◽  
Regulatory Factor

Synergistic actions between all-trans-retinoic acid (atRA) and interferon γ (IFNγ) on modulation of cellular functions have been reported both in vitro and in vivo. However, the mechanism of atRA-mediated regulation of IFNγ signaling is poorly understood. In this study, we have used the human lung epithelial cell line A549 to examine the effect of atRA on IFNγ-induced expression of IFN regulatory factor-1 (IRF-1), an important transcription factor involved in cell growth and apoptosis, differentiation, and antiviral and antibacterial immune responses. At least 4 h of pretreatment with atRA followed by suboptimal concentrations of IFNγ induced a faster, higher, and more stable expression of IRF-1 than IFNγ alone. Actinomycin D completely blocked the induction of IRF-1 by the combination, suggesting regulation at the transcriptional level. Further, we found that activation of signal transducer and activator of transcription-1 was induced more dramatically by atRA and IFNγ than by IFNγ alone. Expression of IFNγ receptor-1 on the cell surface was also increased upon atRA pretreatment. Experiments using receptor-selective retinoids revealed that ligands for retinoic acid receptor-α (RARα), including atRA, 9-cis-retinoic acid, and Am580, sequentially increased the levels of IFNγ receptor-1, activated signal transducer and activator of transcription-1, and IRF-1 and that an RARα antagonist was able to inhibit the effects of atRA and Am580. In addition, atRA pretreatment affected the transcriptional functions of IFNγ-induced IRF-1, increasing its nuclear localization and DNA binding activity as well as the transcript levels of IRF-1 target genes. These results suggest that atRA, an RARα ligand, regulates IFNγ-induced IRF-1 by affecting multiple components of the IFNγ signaling pathway, from the plasma membrane to the nuclear transcription factors.

scholarly journals Lithium Modulates Autophagy in Esophageal and Colorectal Cancer Cells and Enhances the Efficacy of Therapeutic Agents In Vitro and In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0134676 ◽  
Author(s):  
Tracey R. O’Donovan ◽  
Simon Rajendran ◽  
Seamus O’Reilly ◽  
Gerald C. O’Sullivan ◽  
Sharon L. McKenna
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Therapeutic Agents ◽  
Colorectal Cancer Cells

scholarly journals Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

2021 ◽  
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
High Level ◽  
The Impact

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

scholarly journals A new coactivator complex required for retinoic acid-dependent regulation of embryonic symmetry

2016 ◽  
Author(s):  
Goncalo C. Vilhais-Neto ◽  
Marjorie Fournier ◽  
Jean-Luc Plassat ◽  
Mihaela E. Sardiu ◽  
Anita Saraf ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Rna Polymerase Ii ◽  
Protein Complex ◽  
Target Genes ◽  
Bilateral Symmetry ◽  
Molecular Control ◽  
Mouse Mutants ◽  
Proteomic Approach

Bilateral symmetry is a striking feature of the vertebrate body plan organization. Vertebral precursors, called somites, provide one of the best illustrations of embryonic symmetry. Maintenance of somitogenesis symmetry requires Retinoic acid (RA) and its coactivator Rere/Atrophin2. Here, using a proteomic approach we identify a protein complex, containing Wdr5, Hdac1, Hdac2 and Rere (named WHHERE), which regulates RA signalling and controls embryonic symmetry. We demonstrate that Wdr5, Hdac1 and Hdac2 are required for RA signalling in vitro and in vivo. Mouse mutants for Wdr5 and Hdac1 exhibit asymmetrical somite formation characteristic of RA-deficiency. We also identify the Rere-binding histone methyltransferase Ehmt2/G9a, as a RA coactivator controlling somite symmetry. Upon RA treatment, WHHERE and Ehmt2 become enriched at RA target genes to promote RNA Polymerase II recruitment. Our work identifies a novel protein complex linking key epigenetic regulators acting in the molecular control of embryonic bilateral symmetry.

scholarly journals Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Claudia M. Kowolik ◽  
Min Lin ◽  
Jun Xie ◽  
Larry E. Overman ◽  
David A. Horne
Keyword(s):  
Pancreatic Cancer ◽  
Liver Metastasis ◽  
Tumor Growth ◽  
Cell Lines ◽  
Target Genes ◽  
Pancreatic Cancer Cell ◽  
Standard Of Care ◽  
Therapeutic Agents ◽  
Survival Times

Abstract Background Pancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer. Methods We characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo. Results NT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine. Conclusions Favorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease.

Retinoic acid action is altered within endometrium of baboons affected with endometriosis

2022 ◽  
pp. 228402652110620
Author(s):  
Mary Ellen Pavone ◽  
Allison R Grover ◽  
Rafael Confino ◽  
Elizabeth K Pearson ◽  
Saurabh Malpani ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Menstrual Cycle ◽  
Disease Progression ◽  
Cell Fate ◽  
Cellular Response ◽  
Target Genes ◽  
Baboon Model ◽  
Disease Induction

Objective: Using a baboon model, we determined the changing expression of Retinoic Acid (RA) target genes during the menstrual cycle and during disease progression. This change could explain the cellular response and changes characteristic of endometriosis. In previous studies, we established that endometriosis affects the CRABP2:FABP5 ratio in an in vitro environment, shifting toward apoptosis and differentiation with higher CRABP2, and anti-apoptosis with higher levels of FABP5. Intervention(s): Endometriosis was induced in female baboons with intraperitoneal inoculation of menstrual endometrium ( n = 2–4). Tissue was harvested via endometrectomy during different stages of the menstrual cycle as well at 3, 6, and 12 month timepoints after inoculation with endometriosis. Main outcome measure(s): Real time PCR was used to quantify STRA6 (a gene responsible for retinol uptake), CRABP2 (a gene necessary for apoptotic and anti-apoptotic estrogenic RA effects), and FABP5 (a gene that mediates the anti-apoptotic actions of RA). Results: STRA6 and CRABP2 expression were highest in the proliferative phase and lowest in the late secretory phase. FABP5 expression remained stable throughout the 12 months following the induction of the disease, whereas STRA6 and CRABP2 continued to decrease during the same period. Conclusions: Our study confirms that a shift in the CRABP2:FABP5 ratio has similar in vivo effects as it does in vitro: changing RA expression with disease induction and progression. As CRABP2 may be important in determining cell fate in the endometrium, gene expression changes could contribute to the anti-apoptotic behavior of affected cells. As expression changes more during progression, earlier rather than later treatment becomes more critical in reducing the rate of disease progression.

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