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Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets
Abstract and Figures
Significance
The beneficial health effects of dietary phytochemicals make them promising candidates for treatment and prevention of multiple diseases. However, cellular targets for dietary components remain largely unknown. By combining phage display with high-throughput sequencing, we identified 160 human targets of apigenin, a flavonoid abundant in fruits and vegetables. The apigenin targets include hnRNPA2, a factor associated with numerous cellular malignancies and involved in mRNA metabolism/splicing. We show that, by inhibiting hnRNPA2 dimerization, apigenin affects the alternative splicing of key mRNAs. These findings provide a perspective on how dietary phytochemicals function and what distinguishes their action from pharmaceutical drugs.
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... This study further showed that RGMa inhibition was correlated with a reduction in Smad3 phosphorylation [21]. A study by Arango et al. utilized second-generation (PD) sequencing, a method that discovers small molecule-protein interactions, to identify RGMa as a target gene for apigenin [22]. In another study, Gao et al. found that apigenin improves hypertension in spontaneously hypertensive rats by down-regulating NADPH oxidase-dependent ROS expression [23]. ...
... This study further showed that RGMa inhibition was correlated with a reduction in Smad3 phosphorylation [21]. A study by Arango et al. utilized secondgeneration (PD) sequencing, a method that discovers small molecule-protein interactions, to identify RGMa as a target gene for apigenin [22]. In another study, Gao et al. found that apigenin improves hypertension in spontaneously hypertensive rats by down-regulating NADPH oxidase-dependent ROS expression [23]. ...
Hypertension is the leading remediable risk factor for cardiovascular morbidity and mortality in the United States. Excess dietary salt consumption, which is a catalyst of hypertension, initiates an inflammatory cascade via activation of antigen-presenting cells (APCs). This pro-inflammatory response is driven primarily by sodium ions (Na+) transporting into APCs by the epithelial sodium channel (ENaC) and subsequent NADPH oxidase activation, leading to high levels of oxidative stress. Oxidative stress, a well-known catalyst for hypertension-related illness development, disturbs redox homeostasis, which ultimately promotes lipid peroxidation, isolevuglandin production and an inflammatory response. Natural medicinal compounds derived from organic materials that are characterized by their anti-inflammatory, anti-oxidative, and anti-mutagenic properties have recently gained traction amongst the pharmacology community due to their therapeutic effects. Flavonoids, a natural phenolic compound, have these therapeutic benefits and can potentially serve as anti-hypertensives. Flavones are a type of flavonoid that have increased anti-inflammatory effects that may allow them to act as therapeutic agents for hypertension, including diosmetin, which is able to induce significant arterial vasodilation in several different animal models. This review will focus on the activity of flavones to illuminate potential preventative and potential therapeutic mechanisms against hypertension.
... However, despite remarkable effectiveness in the head and neck area, induction chemotherapy is not enough to eradicate oral squamous cell carcinomas in all cases (Shah and Gil. 2009) [6]. ...
... A significant decline of apigenin-induced cell growth has been found in the tongue oral cancer-derived cell line. Apigenin treatment leads to cell-cycle arrest at both G0/G1 and G2/M checkpoints (Maggioni et al. 2013) and it shows antitumor activities through regulating multiple signaling pathways containing PI3K/AKT, NF-kB, Wnt/β-catenin, JAK/STATs, MAPK/ERK, AMPK and JNK (Arango et al. 2013) [11]. ...
Globally, oral cancer (OC) is one of the most prevalent malignancies with a negligible prognosis, a high recurrence rate, and high therapeutic costs. Despite many efforts to resolve these issues, no alternative definitively effective solution has yet been presented. From this point of view, it seems necessary to research other new therapeutic methods. Antioxidants are oxidation inhibitors demonstrating diverse physiological functions in the body. In this review, we focused on some compounds that, despite their antioxidant properties, have evidenced anti-cancerous effects on OCs.
... MUC1-CT has become a promising druggable target for treating cancer patients in preclinical models [31][32][33]. Even though the small molecule apigenin was reported to inhibit MUC1-CT dimerisation in the breast cancer cell lines, the inhibitory effect was probably mediated by blocking other targets [34][35][36][37]. Finding new small molecules directly blocking MUC1-CT will offer novel opportunities to treat MUC1-dependent lung tumours. ...
... Currently, no small molecules were reported to target oncogenic MUC1 directly. Even though small molecule apigenin was reported to inhibit MUC1-CT dimerisation in the breast cancer cell lines, the inhibitory effect was probably mediated by blocking other direct targets such as heterogeneous nuclear ribonucleoprotein A2 and the oncogenic signalling pathways [34][35][36]. Our study was the first to describe the intrinsic metabolite AICAR physically binding and targeting MUC1 to induce lung tumour cell apoptosis. ...
Background:
Lung cancer cells overexpress mucin 1 (MUC1) and active subunit MUC1-CT. Although a peptide blocks MUC1 signalling, metabolites targeting MUC1 are not well studied. AICAR is a purine biosynthesis intermediate.
Methods:
Cell viability and apoptosis were measured in AICAR-treated EGFR-mutant and wild-type lung cells. AICAR-binding proteins were evaluated by in silico and thermal stability assays. Protein-protein interactions were visualised by dual-immunofluorescence staining and proximity ligation assay. AICAR-induced whole transcriptomic profile was determined by RNA sequencing. EGFR-TL transgenic mice-derived lung tissues were analysed for MUC1 expression. Organoids and tumours from patients and transgenic mice were treated with AICAR alone or in combination with JAK and EGFR inhibitors to evaluate treatment effects.
Results:
AICAR reduced EGFR-mutant tumour cell growth by inducing DNA damage and apoptosis. MUC1 was one of the leading AICAR-binding and degrading proteins. AICAR negatively regulated JAK signalling and JAK1-MUC1-CT interaction. Activated EGFR upregulated MUC1-CT expression in EGFR-TL-induced lung tumour tissues. AICAR reduced EGFR-mutant cell line-derived tumour formation in vivo. Co-treating patient and transgenic mouse lung-tissue-derived tumour organoids with AICAR and JAK1 and EGFR inhibitors reduced their growth.
Conclusions:
AICAR represses the MUC1 activity in EGFR-mutant lung cancer, disrupting protein-protein interactions between MUC1-CT and JAK1 and EGFR.
... Given that hnRNP A2/B1 is overexpressed in a variety of cancers, the development of drugs targeting hnRNP A2/B1 is of great significance. Previous studies have shown that both Apigenin and Moracin-O-Derived MO-460 can bind to glycine-rich domain fragments at the C-terminal of hnRNPA2 [13][14][15]. L-norleucine can bind the RNA recognition motif (RRM) of hnRNPA2/B1 to play an anti-tumor effect, but whether L-Norleucine binds hnRNPA2/B1 protein in cells has not been verified [16]. As an RNA-binding protein, hnRNPA2/B1 functions through its RRM. ...
Heterogeneous nuclear ribonucleoprotein A2, as an RNA binding protein, participates in the processing and metabolism of RNA molecules. HnRNPA2 is overexpressed in a variety of cancer cells and promotes cancer cell proliferation, which is a potential drug target for tumor therapy. However, few ligands that specifically target A2 protein and inhibit its function have been reported. In this study, a variety of small molecule compounds that can interact with A2 protein were screened from natural and synthetic compounds libraries using computer virtual screening technology and BIAcore high-throughput screening system. In many ways, such as isothermal tiorimetry calorimetry, fluorescence quenching assay, molecular docking simulation and cellular thermal shift assay, we confirmed the interactions between small molecule compounds EpimedinA1, G38 and hnRNPA2 proteins, respectively. Cell experiments showed that G38 inhibited the proliferation of MCF-7 cells and MDA-MB-231 cells in a dose-dependent manner. Furthermore, A2 knockout in breast cancer cells significantly down-regulated cell sensitivity to G38, suggesting that G38 targets A2 protein and inhibits cell proliferation. Our study identified a number of small molecule compounds that may bind to A2 protein and confirmed that G38 inhibits the proliferation of breast cancer cells by binding hnRNPA2 protein, providing a potential targeted drug for clinical treatment of hnRNPA2 overexpressed diseases.
... As apigenin is a polyphenolic compound, it was initially suggested that the mechanism of action would be through its antioxidant property. However, Arango and co-workers described that apigenin impairs the EVA71 RNA association with host factors, such as hnRNP proteins compromising the first translation of the viral genome (Arango et al. 2013). ...
Enteroviruses are pathogens responsible for several diseases, being enterovirus A71 (EVA71) the second leading cause of hand, foot, and mouth disease (HFMD), especially in Asia–Pacific countries. HFMD is mostly common in infants and children, with mild symptoms. However, the disease can result in severe nervous system disorders in children as well as in immunosuppressed adults. The virus is highly contagious, and its transmission occurs via fecal–oral, oropharyngeal secretions, and fomites. The EVA71 burdens the healthy systems and economies around the world, however, up to date, there is no antiviral approved to treat infected individuals and the existent vaccines are not available or approved to be used worldwide. In this context, an extensive literature research was conducted to describe and summarize the recent advances in natural and/or synthetic compounds with antiviral activity against EVA71. The summarized data presented here might simply encourage the future studies in EVA71 antiviral development, by encouraging further research encompassing these compounds or even the application of the techniques and technologies to improve or produce new antiviral molecules.
... Cancer cells are abnormally immortal, they resist their programmed death (apoptosis). A study shows that the apigenin in parsley allows cancer cells to become lethal again [124]. In addition to its antioxidant power, apigenin in parsley may help regulate blood sugar levels [125]. ...
Spices and aromatic plants are products of plant origin used in food. They are used for the preparation of remedies, for seasoning dishes or for preserving food. This review takes stock of the diversity of spices and aromatic herbs, the chemical composition, the different properties and forms of use of six spices and aromatic herbs commonly used in Benin and around the world. These are Zingiber officinalis (ginger), Curcuma longa (curcuma), Syzygium aro-maticum (clove) and three aromatic herbs Petroselinum crispum (parsley), Rosmarinus officinalis (rosemary), and Laurus nobilis (laurel). The methodology used is that of documentary research oriented towards the consultation of previous scientific documents that have highlighted the different pharmacological activities of the different species of spices and aromatic plants targeted. It is important to note that more than twenty plant species are used as spices and aromatic plants in Benin and around the world. Chemically, these different spices and aromatic herbs contain certain secondary metabo-lites such as flavonoids, tannins, coumarins, alkaloids, steroids, terpenes, sa-ponins, and polyphenols. This diversity of secondary metabolites alone or in a possible synergy may be responsible for many beneficial properties attributed to spices and aromatic herbs.
... Therefore, exploring inhibitors of the inflammatory regulators such as NLRP3 might represent a promising strategy for the treatment of NAFLD and atherosclerosis. Apigenin (APN) is a natural bioflavonoid and is abundant in fruits, vegetables, herbs and spices 17 . APN has been shown to exert diverse pharmacological activities such as anti-inflammatory activity 18 , antioxidant 19 , and antitumor activities 20 . ...
Apigenin (APN), a flavone found in several plant foods with various biological properties such as anti-obesity, anti-inflammation and other abilities, alleviates atherosclerosis and non-alcoholic fatty liver disease (NAFLD) induced by a high fat diet (HFD) in mice. However, the underlying mechanisms have not been fully understood. In this study, we investigated the role of NLRP3 in anti-atherosclerosis and anti-NAFLD effect of APN in mouse models with NLRP3 deficiency. Atherosclerosis and NAFLD models were established by treatment of low density lipoprotein receptor-deficient (Ldlr−/−) mice and NLRP3−/− Ldlr−/− mice with a HFD diet (20% fat and 0.5% cholesterol) with or without APN. En face lipid accumulation analysis, plasma lipid levels, hepatic lipid accumulation and inflammation were analyzed and quantified. For in vitro experiments, HepG2 cells were stimulated by LPS plus oleic acid (OA) in the absence or presence of APN (50 μM). Lipid accumulation and the effect of APN on the NLRP3/NF-κB signaling pathway were investigated. APN administration partly reversed atherosclerosis and hepatic lipid accumulation, and decreased body weight and plasma lipid levels in Ldlr−/− mice when fed a HFD. Compared with Ldlr−/− mice, NLRP3−/− Ldlr−/− mice showed more severe atherosclerosis and hepatic lipid accumulation. Treating the HepG2 cells with APN reduced lipid accumulation. APN also inhibited activation of the NLRP3/ NF-κB signaling pathway stimulated by OA together with LPS. Our results indicate that APN supplementation prevents atherosclerosis and NAFLD via NLRP3 inhibition in mice, and suggest that APN might be a potential therapeutic agent for the prevention of atherosclerosis and NAFLD.
... Regulation of hnRNP-driven splicing events can be potential targets of anti-cancer agents. For instance, we showed that the flavone apigenin, which associates directly with hnRNPA2, reverted the splicing of c-FLIP and CASP9 to their respective pro-apoptotic variants found in non-carcinogenic cells [136]. Similarly, apigenin sensitized lung cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by increasing the protein levels of the TRAIL receptor (DR5) and reducing the expression of c-FLIP through AS rewiring. ...
Cancer remains the second leading cause of death, accounting for approximately 20% of all fatalities. Evolving cancer cells and a dysregulated immune system create complex tumor environments that fuel tumor growth, metastasis, and resistance. Over the past decades, significant progress in deciphering cancer cell behavior and recognizing the immune system as a hallmark of tumorigenesis has been achieved. However, the underlying mechanisms controlling the evolving cancer-immune landscape remain mostly unexplored. Heterogeneous nuclear ribonuclear proteins (hnRNP), a highly conserved family of RNA-binding proteins, have vital roles in critical cellular processes, including transcription, post-transcriptional modifications, and translation. Dysregulation of hnRNP is a critical contributor to cancer development and resistance. HnRNP contribute to the diversity of tumor and immune-associated aberrant proteomes by controlling alternative splicing and translation. They can also promote cancer-associated gene expression by regulating transcription factors, binding to DNA directly, or promoting chromatin remodeling. HnRNP are emerging as newly recognized mRNA readers. Here, we review the roles of hnRNP as regulators of the cancer-immune landscape. Dissecting the molecular functions of hnRNP will provide a better understanding of cancer-immune biology and will impact the development of new approaches to control and treat cancer.
Recent advances in our understanding of plant metabolism have highlighted the significance of specialized metabolites in the regulation of gene expression associated with biosynthetic networks. This opinion article focuses on the molecular mechanisms of small-molecule-mediated feedback regulation at the transcriptional level and its potential modes of action, including metabolite signal perception, the nature of the sensor, and the signaling transduction mechanisms leading to transcriptional and post-transcriptional regulation, based on evidence available from plants and other kingdoms of life. We also discuss the challenges associated with identifying the occurrences, effects, and localization of small molecule-protein interactions. Further understanding of small-molecule-controlled metabolic fluxes will enable rational design of transcriptional regulation systems in metabolic engineering to produce high-value specialized metabolites.
Apigenin, a flavonoid widely existed in vegetables and fruits, possesses anticarcinogenic, low toxicity and no mutagenic properties, suggesting that apigenin is a potential therapeutic agent for tumor. However, the underlying anti-cancer molecular target of apigenin is still unclear. Therefore, to reveal the direct target and amino acid site of apigenin against colorectal cancer is the focus of this study. In present study, the results proved that the anti-CRC activity of apigenin was positively correlated with pyruvate kinase M2 (PKM2) expression, characterized by the inhibition of cell proliferation and increase of apoptotic effects induced by apigenin in LS-174T cells of knock down PKM2. Next, pull-down and MALDI-TOF/TOF analysis determined that apigenin might interact directly with PKM2 in HCT-8 cells. Further, the study confirmed that lysine residue 433 (K433) was a key amino acid site for PKM2 binding to apigenin. Apigenin restricted the glycolysis of LS-174T and HCT-8 cells by targeting K433 site of PKM2, thereby playing an anti-CRC role in vivo and in vitro. Meanwhile, apigenin markedly attenuated tumor growth without any adverse effects. Taken together, these findings reveal that apigenin is worthy of consideration as a promising PKM2 inhibitor for the prevention of CRC.
DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here, we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq), and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and autoregulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells.
A random library of phage displayed peptides was screened for binding to a biotinylated derivative of paclitaxel (Taxol). Affinity-selected peptides were analyzed for similarity to human proteins. There was no significant similarity between the paclitaxel-selected peptides and tubulin. However, a subset of the peptides was identified that exhibits significant similarity to a non-conserved region of the anti-apoptotic human protein Bcl-2: ELISA assays confirmed binding of paclitaxel to Bcl-2, and circular dichroism spectroscopy demonstrated that a substantial conformational change accompanies this binding. In vivo, treatment with paclitaxel has been shown to lead to Bcl-2 inactivation with concomitant phosphorylation of residues in a disordered, regulatory loop region of the protein. Similarity between paclitaxel-selected peptides and this loop region implicate these residues in drug binding, and suggest that the apoptotic action of paclitaxel may involve the binding of paclitaxel to Bcl-2. These results demonstrate that peptides displayed on the surface of bacteriophage particles can mimic the ligand-binding properties of disordered regions of proteins.
Biosynthesis of UDP-glucuronic acid by UDP-glucose 6-dehydrogenase (UGDH) occurs through the four-electron oxidation of the
UDP-glucose C6 primary alcohol in two NAD+-dependent steps. The catalytic reaction of UGDH is thought to involve a Cys nucleophile that promotes formation of a thiohemiacetal
enzyme intermediate in the course of the first oxidation step. The thiohemiacetal undergoes further oxidation into a thioester,
and hydrolysis of the thioester completes the catalytic cycle. Herein we present crystallographic and kinetic evidence for
the human form of UGDH that clarifies participation of covalent catalysis in the enzymatic mechanism. Substitution of the
putative catalytic base for water attack on the thioester (Glu161) by an incompetent analog (Gln161) gave a UGDH variant (E161Q) in which the hydrolysis step had become completely rate-limiting so that a thioester enzyme
intermediate accumulated at steady state. By crystallizing E161Q in the presence of 5 mm UDP-glucose and 2 mm NAD+, we succeeded in trapping a thiohemiacetal enzyme intermediate and determined its structure at 2.3 Å resolution. Cys276 was covalently modified in the structure, establishing its role as catalytic nucleophile of the reaction. The thiohemiacetal
reactive C6 was in a position suitable to become further oxidized by hydride transfer to NAD+. The proposed catalytic mechanism of human UGDH involves Lys220 as general base for UDP-glucose alcohol oxidation and for oxyanion stabilization during formation and breakdown of the thiohemiacetal
and thioester enzyme intermediates. Water coordinated to Asp280 deprotonates Cys276 to function as an aldehyde trap and also provides oxyanion stabilization. Glu161 is the Brønsted base catalytically promoting the thioester hydrolysis.
The six "core" proteins of HeLa cell 40S nuclear ribonucleoprotein particles (hnRNP particles) package 700-nucleotide lengths of pre-mRNA into a repeating array of regular particles. We have previously shown that the C proteins exist as anisotropic tetramers of (C1)3C2 in 40S hnRNP particles and that each particle probably contains three such tetramers. We report here that proteins A2 and B1 also exist in monoparticles as (A2)3B1 tetramers and that each monoparticle contains at least three such tetramers. Proteins A2 and B1 dissociate from isolated monoparticles as a stable tetramer upon nuclease digestion. In low-salt gradients, the tetramers sediment at 6.8S, which is consistent with a mass of 145 kDa. In 200 mM salt, the concentration which dissociates these proteins from RNA, only 4.2S dimers exist in solution. Tetramers of (A2)3B1 possess the ability to package multiples of 700 nucleotides of RNA in vitro into an array of regular, 22.5-nm 43S particles. Unlike the in vitro assembly of intact 40S hnRNP, the (A2)3B1 tetramers assemble by means of a highly cooperative process. These findings indicate that the (A2)3B1 tetramers play a major role in hnRNP assembly and they further support the contention that 40S monoparticles are regular structures composed of three copies of three different tetramers, i.e., 3[(A1)3B2, (A2)3B1, (C1)3C2].
Over four thousand flavonoids, based on the C6-C3-C6 skeleton, have been found in plants, and are divided into several classes, i.e., anthocyanins, flavones, flavonols, flavanones, dihydroflavonols, chalcones, aurones, flavan and proanthocyanidins, isoflavonoids, biflavonoids, etc. In this review, the chemical structures of the reported flavonoid classes are introduced and their distribution in nature are described. Additionally, some recent chemotaxonomical examples using the flavonoids are also given.
The heterogeneous nuclear ribonucleoproteins A1, A2/B1 and A3 (hnRNPs A/B) are involved in many nuclear functions that are confined to distinct regions within the nucleus. To characterise and compare the distribution of the hnRNPs A/B in these subnuclear compartments, their colocalisation with spliceosomal components, nascent transcripts and other nuclear markers in HeLa cells was investigated by immunostaining and transfection of GFP constructs. The mechanisms of this localisation were further explored by treating cells with detergent, nucleases and transcription inhibitors. We have also examined the dynamics of A2/B1 throughout the cell cycle. Our results show that hnRNPs A/B have different subnuclear localisations, with A1 differentially localised to the nuclear envelope, and A2/B1 and A3 enriched around nucleoli. This pattern of distribution was dependent on RNA integrity and active transcription. The hnRNPs A/B preferentially colocalised with a subset of splicing factors. Significantly, only rarely did transcription factories colocalise with high levels of these hnRNPs. Moreover, localisation of A2/B1 changed with cell cycle stage. Our findings show that the subnuclear localisation of the hnRNPs A/B is differentially, spatially and temporally regulated, and suggest that this localisation may be relevant to their nuclear functions.
Flavones have reported anti-inflammatory activities, but the ability of flavone-rich foods to reduce inflammation is unclear. Here, we report the effect of flavone glycosylation in the regulation of inflammatory mediators in vitro and the absorption of dietary flavones in vivo.
The anti-inflammatory activities of celery extracts, some rich in flavone aglycones and others rich in flavone glycosides, were tested on the inflammatory mediators tumor necrosis factor α (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lipopolysaccharide-stimulated macrophages. Pure flavone aglycones and aglycone-rich extracts effectively reduced TNF-α production and inhibited the transcriptional activity of NF-κB, while glycoside-rich extracts showed no significant effects. Deglycosylation of flavones increased cellular uptake and cytoplasmic localization as shown by high-performance liquid chromatography (HPLC) and microscopy using the flavonoid fluorescent dye diphenylboric acid 2-aminoethyl ester (DPBA). Celery diets with different glycoside or aglycone contents were formulated and absorption was evaluated in mice fed with 5 or 10% celery diets. Relative absorption in vivo was significantly higher in mice fed with aglycone-rich diets as determined by HPLC-MS/MS (where MS/MS is tandem mass spectrometry).
These results demonstrate that deglycosylation increases absorption of dietary flavones in vivo and modulates inflammation by reducing TNF-α and NF-κB, suggesting the potential use of functional foods rich in flavones for the treatment and prevention of inflammatory diseases.