Licochalcone A (LCA) is a chalcone that is predominantly found in the root of
species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of ...pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome
from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis.
Mitochondria are well known for their important roles in oxidative phosphorylation, amino acid metabolism, fatty acid oxidation and ion homeostasis. Although the effects of mitochondrial dysfunction ...on tumorigenesis in various cancer cells have been reported, the correlation between mitochondrial dysfunction and epithelial-to-mesenchymal transition (EMT) in lung cancer development and metastasis has not been well elucidated. In the present study, the effects of mitochondrial dysfunction on EMT and migration in lung cancer cells were investigated using inhibitors of mitochondrial respiration, oligomycin A and antimycin A. Oligomycin A and antimycin A induced distinct mesenchymal-like morphological features in H23, H1793 and A549 lung cancer cells. In addition, they decreased the expression levels of the epithelial marker protein E-cadherin, but increased the expression levels of the mesenchymal marker proteins Vimentin, Snail and Slug. The results of immunofluorescence staining indicated that oligomycin A and antimycin A downregulated cortical E-cadherin expression and upregulated the expression of Vimentin. In addition, oligomycin A and antimycin A increased the migration and invasion of A549 lung cancer cells, and promoted the expression levels of phosphorylated (p)-protein kinase B (AKT) and p-AMP-activated protein kinase (AMPK). Notably, the production of reactive oxygen species by oligomycin A and antimycin A did not affect the expression of EMT protein markers. Conversely, treatment with the AKT inhibitor wortmannin and the AMPK inhibitor Compound C upregulated E-cadherin and downregulated Vimentin expression. These results suggested that oligomycin A and antimycin A may induce migration and invasion of lung cancer cells by inducing EMT via the upregulation of p-AKT and p-AMPK expression.
A series of CO2-philic terpolymers were prepared by free radical polymerization using three monomers, poly(ethylene glycol) methyl ether methacrylate (PEGMA), methyl methacrylate (MMA), and ...4-hydroxybenzophenone (BPMA), to develop CO2/N2 and CO2/CO separation membranes. The terpolymers, poly(PEGMA-co-MMA-co-BPMA) (PMB), were cast into thin precursor films, which were then crosslinked by a UV-induced photochemical reaction between benzophenone and the alkyl group to produce crosslinked membranes (X-PMB). The gas permeabilities of the X-PMB membranes were influenced by the PEGMA content due to increased CO2 solubility by the polar ether groups of PEGMA. As the content of PEGMA was increased from 60 to 90 wt%, the permeability of CO2 increased from 49.7 to 110.7 barrer. The permeabilities of CO and N2 also increased from 1.92 to 3.68 barrer and from 1.01 to 2.21 barrer, respectively. X-PMB9 with 90 wt% of PEGMA showed the best performance, where CO2 permeability, CO2/N2 selectivity, and CO2/CO selectivity were 110.7 barrer, 49.9, and 30.1, respectively. This membrane performance is comparable to or better than that of a commercially available membrane material, PEBAX, indicating that the X-PMB could be usefully applied to CO2 separation membranes in carbon capture and utilization.
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•A series of crosslinked CO2-philic terpolymer membranes with PEG moiety were prepared.•The crosslinking reaction was carried out using benzophenone photochemistry.•The gas separation properties was controlled by the PEG content of terpolymer.•The crosslinked membranes showed excellent CO2/N2 and CO2/CO separation properties.
Ubiquitin-specific protease 2 (USP2) is a deubiquitinase belonging to the USPs subfamily. USP2 has been known to display various biological effects including tumorigenesis and inflammation. ...Therefore, we aimed to examine the sensitization effect of USP2 in TRAIL-mediated apoptosis. The pharmacological inhibitor (ML364) and siRNA targeting USP2 enhanced TNF-related apoptosis-inducing ligand (TRAIL)-induced cancer cell death, but not normal cells. Mechanistically, USP2 interacted with survivin, and ML364 degraded survivin protein expression by increasing the ubiquitination of survivin. Overexpression of survivin or USP2 significantly prevented apoptosis through cotreatment with ML364 and TRAIL, whereas a knockdown of USP2 increased sensitivity to TRAIL. Taken together, our data suggested that ML364 ubiquitylates and degrades survivin, thereby increasing the reactivity to TRAIL-mediated apoptosis in cancer cells.
Background and Purpose
Endoplasmic reticulum (ER) stress has been implicated in the pathogeneses of insulin resistance and type 2 diabetes, and extracellular signal‐regulated kinase (ERK) antagonist ...is an insulin sensitizer that can restore muscle insulin responsiveness in both tunicamycin‐treated muscle cells and type 2 diabetic mice. The present study was undertaken to determine whether the chemical or genetic inhibition ER stress pathway targeting by ERK results in metabolic benefits in muscle cells.
Experimental Approach
ER stress was induced in L6 myotubes using tunicamycin (5 μg·mL−1) or thapsigargin (300 nM) and cells were transfected with siRNA ERK or AMPKα2. Changes in ER stress and in the ERK and AMPK signalling pathways were explored by Western blotting. The phosphorylation levels of insulin receptor substrate 1 were analysed by immunoprecipitation and using glucose uptake assay.
Key Results
ER stress dampened insulin‐stimulated signals and glucose uptake, whereas treatment with the specific ERK inhibitor U0126 (25 μM) rescued impaired insulin signalling via AMPK activation. In db/db mice, U0126 administration decreased markers of insulin resistance and increased the phosphorylations of Akt and AMPK in muscle tissues.
Conclusions and Implications
Inhibition of ERK signalling pathways by a chemical inhibitor and knockdown of ERK improved AMPK and Akt signallings and reversed ER stress‐induced insulin resistance in L6 myotubes. These findings suggest that ERK signalling plays an important role in the regulation of insulin signals in muscle cells under ER stress.
Evidence suggests that auranofin (AF) exhibits anticancer activity by inhibiting thioredoxin reductase (TrxR). Here, in this study, we have investigated the synergistic effects of AF and morin and ...their mechanism for the anticancer effects focusing on apoptosis in Hep3B human hepatocellular carcinoma cells. We assessed the anticancer activities by annexin V/PI double staining, caspase, and TrxR activity assay. Morin enhances the inhibitory effects on TrxR activity of AF as well as reducing cell viability. Annexin V/PI double staining revealed that morin/AF cotreatment induced apoptotic cell death. Morin enhances AF‐induced mitochondrial membrane potential (ΔΨm) loss and cytochrome c release. Further, morin/AF cotreatment upregulated death receptor DR4/DR5, modulated Bcl‐2 family members (upregulation of Bax and downregulation of Bcl‐2), and activated caspase‐3, ‐8, and ‐9. Morin also enhances AF‐induced reactive oxygen species (ROS) generation. The anticancer effects results from caspase‐dependent apoptosis, which was triggered via extrinsic pathway by upregulating TRAIL receptors (DR4/DR5) and enhanced via intrinsic pathway by modulating Bcl‐2 and inhibitor of apoptosis protein family members. These are related to ROS generation. In conclusion, this study provides evidence that morin can enhance the anticancer activity of AF in Hep3B human hepatocellular carcinoma cells, indicating that its combination could be an alternative treatment strategy for the hepatocellular carcinoma.
4‐O‐methylascochlorin (MAC) is a derivative of ascochlorin, a prenyl‐phenol compound antibiotic isolated from the fungus Ascochyta viciae. MAC induces caspase/poly (ADP‐ribose) polymerase‐mediated ...apoptosis in leukemia cells. However, the effects of MAC on autophagy in cancer cells and the underlying molecular mechanisms remain unknown. Here, we show that MAC induces autophagy in lung cancer cells. MAC significantly induced the expression of autophagy marker proteins including LC3‐II, Beclin1, and ATG7. MAC promoted AMP‐activated protein kinase (AMPK) phosphorylation and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream signalling proteins P70S6K and 4EBP1. The AMPK activator AICAR upregulated LC3‐II expression through the AMPK/mTOR pathway similar to the effects of MAC. MAC‐induced LC3‐II protein expression was slightly reduced in AMPK siRNA transfected cells. MAC upregulated hypoxia‐inducible factor‐1α (HIF‐1α) and BNIP3, which are HIF‐1α‐dependent autophagic proteins. Treatment with CoCl2, which mimics hypoxia, induced autophagy similar to the effect of MAC. The HIF‐1α inhibitor YC‐1 and HIF‐1α siRNA inhibited the MAC‐induced upregulation of LC3‐II and BNIP3. These results suggest that MAC induces autophagy via the AMPK/mTOR signalling pathway and by upregulating HIF‐1α and BNIP3 protein expression in lung cancer cells.
Sirt1, a key regulator of metabolism and longevity, has recently been implicated in the regulation of allergic reactions, although the underlying mechanism remains unclear. Here we show that Sirt1 ...negatively regulates FcεRI-stimulated mast cell activation and anaphylaxis through two mutually regulated pathways involving AMP-activated protein kinase (AMPK) and protein tyrosine phosphatase 1B (PTP1B). Mast cell-specific knockout of Sirt1 dampened AMPK-dependent suppression of FcεRI signaling, thereby augmenting mast cell activation both in vitro and in vivo. Sirt1 inhibition of FcεRI signaling also involved an alternative component, PTP1B, which attenuated the inhibitory AMPK pathway and conversely enhanced the stimulatory Syk pathway, uncovering a novel role of this phosphatase. Moreover, a Sirt1 activator resveratrol stimulated the inhibitory AMPK axis, with reciprocal suppression of the stimulatory PTP1B/Syk axis, thus potently inhibiting anaphylaxis. Overall, our results provide a molecular explanation for the beneficial role of Sirt1 in allergy and underscore a potential application of Sirt1 activators as a new class of anti-allergic agents.
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