Tumor-suppressive activity of retinoic acid receptor-β in cancer

Xu, Xiao Chun

doi:10.1016/j.canlet.2006.11.019

Cited by 119 publications

(92 citation statements)

References 89 publications

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“…Retinoid signals are transduced primarily through the ligand activation of two families of nuclear retinoid receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). In the past two decades, RARβ has attracted much more attention due to findings of frequent loss of RARβ expression in various types of cancer including colon cancer, reduction of cell responsiveness to retinoid-mediated growth inhibition, or increase in the degree of tumorigenicity by knockdown RARβ gene or blockage of its expression using an antisense strategy [4,23]. Unlike 9-cis retinoic acid, ATRA only activates RARs, which makes it an ideal model for the study of retinoid resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Retinoids, a group of structural and functional analogs of vitamin A, regulate several essential biological processes. Pharmacologically, they have been recognized as important in modulating cell differentiation and apoptosis and in suppressing carcinogenesis in a broad range of tissue types, including CRC in vitro, in animal models and in clinical trials [3,4]. In contrast to the reported beneficial clinical effects, there is evidence that intrinsic or acquired resistance can limit retinoid clinical activity.…”

Section: Introductionmentioning

confidence: 99%

“…All of this evidence led us to hypothesize that celecoxibinduced suppression of COX-2 could improve the effectiveness of retinoids. In addition, the level of COX-2 has been reported to negatively correlate with retinoic acid receptor beta (RARβ) [13][14][15], the level of which has been proved to strongly connect to retinoid sensitivity [4]. However, a study conducted by Mernitz failed to confirm this correlation [16].…”

Section: Introductionmentioning

confidence: 99%

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Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Liu

Zheng

et al. 2010

Cellular and Molecular Biology Letters

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Abstract:Retinoid resistance has limited the clinical application of retinoids as differentiation-inducing and apoptosis-inducing drugs. This study was designed to investigate whether celecoxib, a selective COX-2 inhibitor, has effects on retinoid sensitivity in human colon cancer cell lines, and to determine the possible mechanism of said effects. Cell viability was measured using the MTT assay. Apoptosis was detected via Annexin-V/PI staining and the flow cytometry assay. PGE 2 production was measured with the ELISA assay. The expression of RARβ was assayed via western blotting. The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines. Further study showed the ATRA and celecoxib combination induced greater apoptosis, but that the addition of PGE 2 did not affect the enhanced growth-inhibitory and apoptosis-inducing effects of the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA in the two cell lines. Western blotting showed that the expression of RARβ in HT-29 cell lines was increased by celecoxib, but not by NS398, and that the addition of PGE 2 did not affect the celecoxib-induced expression of the retinoic acid receptor beta. In conclusion, celecoxib increased the expression of RARβ and the level of cellular ATRA sensitivity through COX-2-independent mechanisms. This finding may provide a potential strategy for combination therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Liu

Zheng

et al. 2010

Cellular and Molecular Biology Letters

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“…24 RARB is suppressed also in various other human cancers. 25 Many melanoma cells are resistant to the anti-proliferative effects of ATRA, and positive correlations between the anti-proliferative activity of ATRA and expression of RARB have been confirmed. However, no strict correlation was found between the methylation status of the RARB gene and its expression in melanoma cell lines.…”

Section: Rar-b2 (Retinoic Acid Receptor-b2)mentioning

confidence: 92%

Epigenetic regulation in human melanoma: past and future

Sarkar

Leung

Baguley³

et al. 2015

Epigenetics

246

174

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“…47 Given this selectivity for RARβ, EC19 represents an excellent starting point for further structural optimisation. Few examples of RARβ-selective retinoids containing this metacarboxylate motif exist in the literature, 3,26 and given confirmed links between RARβ and the treatment of cancers (among other conditions), 4,[48][49][50] such a scaffold would be interesting to explore, particularly since the synthetic methodology associated with similar compounds is well understood. 9,21,51 Finally, as might be expected, the methyl ester of EC23 exhibited reduced binding affinity compared to the parent compound, particularly for RARγ (Table 3).…”

Section: Receptor Binding Assaysmentioning

confidence: 99%

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

et al. 2017

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. (2017) 'The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors. ', MedChemComm., 8 (3). pp. 578-592. Further information on publisher's website:https://doi.org/10.1039/C6MD00680APublisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARα, β and γ) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARα/γ but is well-suited to the larger RARβ binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARβ, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described ...

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Tumor-suppressive activity of retinoic acid receptor-β in cancer

Cited by 119 publications

References 89 publications

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Epigenetic regulation in human melanoma: past and future

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

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