Dataset Information

Molecular Mechanism for Cellular Response to ?-Escin and Its Therapeutic Implications.

ABSTRACT: ?-escin is a mixture of triterpene saponins isolated from the horse chestnut seeds (Aesculus hippocastanum L.). The anti-edematous, anti-inflammatory and venotonic properties of ?-escin have been the most extensively clinically investigated effects of this plant-based drug and randomized controlled trials have proved the efficacy of ?-escin for the treatment of chronic venous insufficiency. However, despite the clinical recognition of the drug its pharmacological mechanism of action still remains largely elusive. To determine the cellular and molecular basis for the therapeutic effectiveness of ?-escin we performed discovery and targeted proteomic analyses and in vitro evaluation of cellular and molecular responses in human endothelial cells under inflammatory conditions. Our results demonstrate that in endothelial cells ?-escin potently induces cholesterol synthesis which is rapidly followed with marked fall in actin cytoskeleton integrity. The concomitant changes in cell functioning result in a significantly diminished responses to TNF-? stimulation. These include reduced migration, alleviated endothelial monolayer permeability, and inhibition of NF?B signal transduction leading to down-expression of TNF-?-induced effector proteins. Moreover, the study provides evidence for novel therapeutic potential of ?-escin beyond the current vascular indications.

SUBMITTER: Domanski D

PROVIDER: S-EPMC5058498 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Molecular Mechanism for Cellular Response to β-Escin and Its Therapeutic Implications.

Domanski Dominik D Zegrocka-Stendel Oliwia O Perzanowska Anna A Dutkiewicz Malgorzata M Kowalewska Magdalena M Grabowska Iwona I Maciejko Dorota D Fogtman Anna A Dadlez Michal M Koziak Katarzyna K

PloS one 20161011 10

β-escin is a mixture of triterpene saponins isolated from the horse chestnut seeds (Aesculus hippocastanum L.). The anti-edematous, anti-inflammatory and venotonic properties of β-escin have been the most extensively clinically investigated effects of this plant-based drug and randomized controlled trials have proved the efficacy of β-escin for the treatment of chronic venous insufficiency. However, despite the clinical recognition of the drug its pharmacological mechanism of action still remain ...[more]

PMID: 27727329

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Project description:Development of targeted therapy for hepatocellular carcinoma (HCC) remains a major challenge. We have recently identified an elevated expression of the fifth subunit of COP9 signalosome (CSN5) in early HCC as compared to dysplastic stage. In the present study, we explored the possibility of CSN5 being a potential therapeutic target for HCC. We demonstrate that CSN5 knockdown by small interfering (si) RNA caused a block in cell proliferation and cell cycle progression, and induced apoptosis of HCC cells in vitro. The transcriptomic analysis of CSN5 knockdown signature by microarray showed that the anti-proliferative effect was driven by a common subset of molecular alterations including downregulation of CDK6 or ITGB1, which are involved in cell cycle regulation or tumor invasion and functionally interconnected with key oncogenic regulators such as TGFβ1 and MYC. Western blot assay showed that CSN5 depletion significantly increases the phosphorylation of Smad2/3 and decreases the expression of ITGB1, CDK6 and cyclin D1 proteins, restoring the tumor suppressive function of RB and thereby contributing to inhibition of cell cycle progression. In addition, CSN5 knockdown increased the expression of Bak but decreased the level of Bcl-2, subsequently leading to apoptosis through the activation of caspase-3. A chemically modified variant of CSN5 siRNA was then selected for in vivo application based on the growth inhibitory effect and minimal induction of unwanted immune response. Systemic delivery of the CSN5 3/8 variant by stable-nucleic-acid-lipid-particles (SNALP) significantly suppressed the tumor growth in Huh7-luc+ orthotopic xenograft model. Taken together, these results indicate that CSN5 plays a pivotal role in HCC pathogenesis and maybe an attractive molecular target for systemic HCC therapy. Huh7 and HepG2 cells were treated with CSN5 siRNA and negative control siRNA for 48 hours and subjected to Illumina microarray analysis. 4 replicates each.

Project description:Development of targeted therapy for hepatocellular carcinoma (HCC) remains a major challenge. We have recently identified an elevated expression of the fifth subunit of COP9 signalosome (CSN5) in early HCC as compared with dysplastic stage. In the present study, we explored the possibility of CSN5 being a potential therapeutic target for HCC. Our results show that CSN5 knockdown by small-interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell-cycle progression in HCC cells in vitro. The down-regulation of CSN5 was sufficient to interfere with CSN function as evidenced by the accumulation of neddylated Cullin 1 and changes in the protein levels of CSN-controlled substrates SKP2, p53, p27 and nuclear factor-κB, albeit to a different degree depending on the HCC cell line, which could account for the CSN5 knockdown phenotype. The transcriptomic analysis of CSN5 knockdown signature showed that the anti-proliferative effect was driven by a common subset of molecular alterations including down-regulation of cyclin-dependent kinase 6 (CDK6) and integrin β1 (ITGB1), which were functionally interconnected with key oncogenic regulators MYC and TGFβ1 involved in the control of proliferation, apoptotic cell death and HCC progression. Consistent with microarray analysis, western blotting revealed that CSN5 depletion increased phosphorylation of Smad 2/3, key mediators of TGFβ1 signaling, decreased the protein levels of ITGB1, CDK6 and cyclin D1 and caused reduced expression of anti-apoptotic Bcl-2, while elevating the levels of pro-apoptotic Bak. A chemically modified variant of CSN5 siRNA was then selected for in vivo application based on the growth inhibitory effect and minimal induction of unwanted immune response. Systemic delivery of the CSN5 3/8 variant by stable-nucleic-acid-lipid particles significantly suppressed the tumor growth in Huh7-luc+ orthotopic xenograft model. Taken together, these results indicate that CSN5 has a pivotal role in HCC pathogenesis and maybe an attractive molecular target for systemic HCC therapy.

Dataset Information

Molecular Mechanism for Cellular Response to ?-Escin and Its Therapeutic Implications.

Publications

Molecular Mechanism for Cellular Response to β-Escin and Its Therapeutic Implications.

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