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Effect of Quercetin on ABCC6 Transporter: Implication in HepG2 Migration.

ABSTRACT: Quercetin is a member of the flavonoid group of compounds, which is abundantly present in various dietary sources. It has excellent antioxidant properties and anti-inflammatory activity and is very effective as an anti-cancer agent against various types of tumors, both in vivo and in vitro. Quercetin has been also reported to modulate the activity of some members of the multidrug-resistance transporters family, such as P-gp, ABCC1, ABCC2, and ABCG2, and the activity of ecto-5'-nucleotidase (NT5E/CD73), a key regulator in some tumor processes such as invasion, migration, and metastasis. In this study, we investigated the effect of Quercetin on ABCC6 expression in HepG2 cells. ABCC6 is a member of the superfamily of ATP-binding cassette (ABC) transporters, poorly involved in drug resistance, whose mutations cause pseudoxanthoma elasticum, an inherited disease characterized by ectopic calcification of soft connective tissues. Recently, it has been reported that ABCC6 contributes to cytoskeleton rearrangements and HepG2 cell motility through purinergic signaling. Gene and protein expression were evaluated by quantitative Reverse-Transcription PCR (RT-qPCR) and western blot, respectively. Actin cytoskeleton dynamics was evaluated by laser confocal microscopy using fluorophore-conjugated phalloidin. Cell motility was analyzed by an in vitro wound-healing migration assay. We propose that ABCC6 expression may be controlled by the AKT pathway as part of an adaptative response to oxidative stress, which can be mitigated by the use of Quercetin-like flavonoids.

SUBMITTER: Abruzzese V

PROVIDER: S-EPMC8069417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inhibition of ABCC6 Transporter Modifies Cytoskeleton and Reduces Motility of HepG2 Cells via Purinergic Pathway.

Project description:ABCC6, belonging to sub-family C of ATP-binding cassette transporter, is an ATP-dependent transporter mainly present in the basolateral plasma membrane of hepatic and kidney cells. Although the substrates transported are still uncertain, ABCC6 has been shown to promote ATP release. The extracellular ATP and its derivatives di- and mono-nucleotides and adenosine by acting on specific receptors activate the so-called purinergic pathway, which in turn controls relevant cellular functions such as cell immunity, inflammation, and cancer. Here, we analyzed the effect of Abcc6 knockdown and probenecid-induced ABCC6 inhibition on cell cycle, cytoskeleton, and motility of HepG2 cells. Gene and protein expression were evaluated by quantitative Reverse Transcription PCR (RT-qPCR) and western blot, respectively. Cellular cycle analysis was evaluated by flow cytometry. Actin cytoskeleton dynamics was evaluated by laser confocal microscopy using fluorophore-conjugated phalloidin. Cell motility was analyzed by in vitro wound-healing migration assay. Cell migration is reduced both in Abcc6 knockdown HepG2 cells and in probenecid treated HepG2 cells by interfering with the extracellular reserve of ATP. Therefore, ABCC6 could contribute to cytoskeleton rearrangements and cell motility through purinergic signaling. Altogether, our findings shed light on a new role of the ABCC6 transporter in HepG2 cells and suggest that its inhibitor/s could be considered potential anti-metastatic drugs.

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Investigation of the anti-cancer effect of quercetin on HepG2 cells in vivo.

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The ABCC6 Transporter: A New Player in Biomineralization.

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Quercetin effect on gene expression in HepG2 hepatocellular cancer cells

Project description:Quercetin is a flavonol modifying numerous cell processes with potent antiproliferative effects on cancer cell-lines. The aim of this study was to explore by gene-array analysis the effect of quercetin on cancer-related gene expression in HepG2 cells, followed by verification with RT-PCR and analysis of the expected phenotypic changes (migration, cell cycle, cell proliferation). Quercetin induces significant changes on cell-adhesion related genes, leading to reduced migratory capacity and disorganization of the actin cytoskeleton. Several genes related to DNA functions, cellular metabolism and signal-transducer activities were also modified, while an early effect on G–protein related cascades possibly via protease-activated receptor 2 and phospholipase C-?1 was identified. Cyclin-D associated events in G1 and ubiquitin-dependent degradation of cyclin-D1 were also affected, resulting in cell-cycle arrest without activation of apoptosis pathways. In conclusion quercetin (3?M) exerts its cellular effects by modifying numerous genes related to mechanisms involved in cancer initiation and promotion. HepG2 cells were serum starved for 24 hours and were then treated with serum free medium with or without quercetin (3?M). Total RNA was collected at 2, 4, 12 and 24 hours and was used for gene-array experiments.

2009-03-11 | E-GEOD-15162 | biostudies-arrayexpress

Inhibitory effect of lingonberry extract on HepG2 cell proliferation, apoptosis, migration, and invasion.

Project description:Lingonberry (Vaccinium vitis-idaea L.) extract contains various active ingredients with strong inhibitory effects on cancer cell growth. HepG2 cells were treated with various concentrations of lingonberry extract, cell inhibition rate was measured by CCK-8 assay, and apoptosis rate by annexin-propidium iodide double-staining assay. The cell cycle was analyzed by flow cytometry, and cell migration and invasion by transwell assay. Real-time reverse transcription-PCR and western blotting were employed to analyze the expression of C-X-C motif chemokine ligand 3 (CXCL3). Ki-67, TUNEL, and transwell assays were used to verify the relationship between CXCL3 expression and cell proliferation, apoptosis, migration, and invasion. The composition of lingonberry extract was: 37.58% cyanidin-3-O-glucoside, 10.96% kaempferol 3-O-arabinoside, 4.52% epicatechin, 4.35% chlorogenic acid, 3.83% catechinic acid, 1.54% isoquercitrin, 1.05% 4-hydroxycinnamon acid, 1.03% cyanidin chloride, 0.85% 2,3-dihydroxybenzoic acid, 0.55% quercetin, 0.36% D-(-)-quininic acid, 0.96% caffeic acid, 0.16% ferulic acid, 0.12% oleanolic acid, and 0.03% ursolic acid. Lingonberry extract inhibited the proliferation of HepG2 cells in a dose-dependent manner. After 48 h exposure to 100 μg/mL extract the inhibition rate and IC50 were 80.89±6.05% and 22.62 μg/mL, respectively. Lingonberry extract promoted late apoptosis in HepG2 cells and arrested the cell cycle at G2/M and S phases. Lingonberry extract also promoted the apoptosis of HepG2 cancer cells, inhibiting their proliferation, migration, and invasion by regulating the expression of CXCL3. This study offers new insight into the antihepatoma activity of lingonberry extract and provides a basis for the development of pilot antitumor drugs.

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Quercetin effect on gene expression in HepG2 hepatocellular cancer cells

Project description:Quercetin is a flavonol modifying numerous cell processes with potent antiproliferative effects on cancer cell-lines. The aim of this study was to explore by gene-array analysis the effect of quercetin on cancer-related gene expression in HepG2 cells, followed by verification with RT-PCR and analysis of the expected phenotypic changes (migration, cell cycle, cell proliferation). Quercetin induces significant changes on cell-adhesion related genes, leading to reduced migratory capacity and disorganization of the actin cytoskeleton. Several genes related to DNA functions, cellular metabolism and signal-transducer activities were also modified, while an early effect on G–protein related cascades possibly via protease-activated receptor 2 and phospholipase C-γ1 was identified. Cyclin-D associated events in G1 and ubiquitin-dependent degradation of cyclin-D1 were also affected, resulting in cell-cycle arrest without activation of apoptosis pathways. In conclusion quercetin (3μM) exerts its cellular effects by modifying numerous genes related to mechanisms involved in cancer initiation and promotion.

2009-03-11 | GSE15162 | GEO

Copy number variation in the ATP-binding cassette transporter ABCC6 gene and ABCC6 pseudogenes in patients with pseudoxanthoma elasticum.

Project description:Single mutations in the ATP-binding cassette transporter (ABCC6) gene (OMIM 603234) are known to cause the rare autosomal recessive disease pseudoxanthoma elasticum (PXE). Recently, we have found that copy number variations (CNVs) in pseudogenes of the ABCC6 gene are quite common. The aim of this study was to investigate the frequency and possible contribution of CNV in ABCC6 and its pseudogenes in PXE. Genomic DNA from 212 PXE individuals were examined for copy number by pyrosequencing and quantitative polymerase chain reaction (PCR) and compared with healthy individuals. The frequency of PXE individuals with any CNV was higher than in healthy individuals. The majority of variation comprised known and possibly new deletions in the ABCC6 gene and duplications of the ABCC6P1 and ABCC6P2 genes. ABCC6 deletions and ABCC6P2 duplications were not observed in 142 healthy individuals. In conclusion, by pyrosequencing and quantitative PCR, we were able to detect known and possibly new deletions in the ABCC6 gene that may have caused the PXE phenotype. Pyrosequencing may be used in PXE patients who have obtained incomplete genotype from conventional techniques. The frequency of ABCC6P2 pseudogene duplication was more common in PXE patients than healthy individuals and may affect the PXE phenotype.

| S-EPMC4444165 | biostudies-literature

Quercetin Directly Interacts with Vitamin D Receptor (VDR): Structural Implication of VDR Activation by Quercetin.

Project description:The vitamin D receptor (VDR) is a member of the nuclear receptor (NR) superfamily. The VDR binds to active vitamin D3 metabolites, which stimulates downstream transduction signaling involved in various physiological activities such as calcium homeostasis, bone mineralization, and cell differentiation. Quercetin is a widely distributed flavonoidin nature that is known to enhance transactivation of VDR target genes. However, the detailed molecular mechanism underlying VDR activation by quercetin is not well understood. We firstdemonstrated the interaction between quercetin and the VDR at the molecular level by using fluorecence quenching and saturation transfer difference (STD) NMR experiments. The dissociation constant (Kd) of quercetin and the VDR was 21.15 ± 4.31 μM, and the mapping of quercetin subsites for VDR binding was performed using STD-NMR. The binding mode of quercetin was investigated by a docking study combined with molecular dynamics (MD) simulation. Quercetin might serve as a scaffold for the development of VDR modulators with selective biological activities.

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