CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38(MAPK), a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21(CIP1/WAF1). These findings establish a function for CD44v in regulation of ROS defense and tumor growth.
Carbon nanotubes (CNTs), tubular molecular entities that consist of sp(2)-hybridized carbon atoms, are currently produced as mixtures that contain tubes of various diameters and different sidewall structures. The electronic and optical properties of CNTs are determined by their diameters and sidewall structures and so a controlled synthesis of uniform-diameter, single-chirality CNTs-a significant chemical challenge-would provide access to pure samples with predictable properties. Here we report a rational bottom-up approach to synthesize structurally uniform CNTs using carbon nanorings (cycloparaphenylenes) as templates and ethanol as the carbon source. The average diameter of the CNTs formed is close to that of the carbon nanorings used, which supports the operation of a 'growth-from-template' mechanism in CNT formation. This bottom-up organic chemistry approach is intrinsically different from other conventional approaches to making CNTs and, if it can be optimized sufficiently, offers a route to the programmable synthesis of structurally uniform CNTs.
Aberrant epithelial-mesenchymal transition (EMT) is involved in development of fibrotic disorders and cancer invasion.Alterations of cell-extracellular matrix interaction also contribute to those pathological conditions. However, the functional interplay between EMT and cell-extracellular matrix interactions remains poorly understood. We now show that the inflammatory mediator tumor necrosis factor-␣ (TNF-␣) induces the formation of fibrotic foci by cultured retinal pigment epithelial cells through activation of transforming growth factor- (TGF-) signaling in a manner dependent on hyaluronan-CD44-moesin interaction. TNF-␣ promoted CD44 expression and moesin phosphorylation by protein kinase C, leading to the pericellular interaction of hyaluronan and CD44. Formation of the hyaluronan-CD44-moesin complex resulted in both cell-cell dissociation and increased cellular motility through actin remodeling. Furthermore, this complex was found to be associated with TGF- receptor II and clathrin at actin microdomains, leading to activation of TGF- signaling. We established an in vivo model of TNF-␣-induced fibrosis in the mouse eye, and such ocular fibrosis was attenuated in CD44-null mice. The production of hyaluronan and its interaction with CD44, thus, play an essential role in TNF-␣-induced EMT and are potential therapeutic targets in fibrotic disorders. The epithelial-mesenchymal transition (EMT)2 of epithelial cells is characterized by the loss of epithelial characteristics and the gain of mesenchymal attributes. During this transition, epithelial cells down-regulate cell-cell adhesion systems, lose their polarity, and acquire a mesenchymal phenotype associated with increased interaction with the extracellular matrix (ECM) and enhanced migratory capacity. The EMT is considered a critical event in metazoan embryogenesis as well as in physiological processes such as wound healing. However, it also plays an important role in pathological settings such as fibrotic disorders in various organs as well as cancer invasion and metastasis.The EMT associated with physiological processes is triggered by members of the transforming growth factor- (TGF-) family of proteins that function as morphogens (1). In vitro studies have also shown that TGF- is the major inducer of the EMT in epithelial cells (2). Fibrotic disorders associated with pathological EMT result from a series of events including inflammation, leukocyte infiltration, and the production of cytokines and growth factors. TGF- is one of the cytokines produced during inflammation and is, therefore, thought to heavily contribute to EMT-associated fibrosis (3). However, given that TGF- also possesses anti-inflammatory properties, the mechanism of pathological EMT induced by the inflammatory response may be multifactorial and differ from that of physiological EMT.In addition to growth factors, changes in the ECM microenvironment contribute to the EMT. Epithelial cells cultured in a type I collagen gel were found to undergo the EMT (4). Furthermore, collagen-induce...
A low concentration (10 nM) of adenosine potentiated hippocampal neuronal activity via A(2a) adenosine receptors without affecting presynaptic glutamate release or postsynaptic glutamatergic conductance. Adenosine inhibited glutamate uptake through the glial glutamate transporter, GLT-1, via A(2a) adenosine receptors. In addition, adenosine stimulated GLT-1-independent glutamate release from astrocytes, possibly in response to a rise in intracellular Ca(2+), via A(2a) adenosine receptors involving PKA activation. Those adenosine actions could lead to an increase in synaptic glutamate concentrations responsible for the potentiation of hippocampal neuronal activity. The results of the present study thus represent a novel neuromodulatory pathway with a glial contribution, bearing both inhibition of GLT-1 function and stimulation of glial glutamate release, as mediated via A(2a) adenosine receptors.
Oxidative stress is regarded as a causative factor in aging and various degenerative diseases. Here, we show the mechanism by which oxidative stress induces disruption of cell-cell junctions using retinal pigment epithelial cells. We demonstrated that reactive oxygen species (ROS)-mediated activation of Src kinase increases the tyrosine phosphorylation state of p120-catenin and rapidly triggers translocation of p120-catenin and internalization of N-cadherin from the cell-cell adhesion sites to an early endosomal compartment. Endosomal accumulation of p120-catenin resulted in stress fiber formation and cell-cell dissociation through the activation of Rho/Rho kinase pathway. However, these cytoskeletal remodeling and cell-cell dissociation induced by oxidative stress were transient, due to the activation of nuclear factor-κB (NF-κB) and the expression of manganese superoxide dismutase (Mn-SOD). Using the NF-κB specific inhibitor DHMEQ, we found that NF-κB is part of a negative feedback loop to control intracellular ROS levels. Finally, we demonstrated that H 2 O 2 treatment alone does not induce the epithelial mesenchymal transition (EMT) in retinal pigment epithelial cells, which can be induced by TNF-α treatment. These findings suggest that oxidative stress is a crucial factor to induce the cell-cell dissociation, an initial step of EMT, but does not provide sufficient signals to establish and to maintain the EMT.
There is no universal method that can be applied to extract bound extracellular polymeric substances (EPS) from benthic diatoms of intertidal sediments without causing cell lysis. Six extraction methods were tested on a diatom culture of Navicula jeffreyi to establish the best compromise between high yields of carbohydrate extraction and minimum cell lysis. Extraction with distilled water provoked cell lysis (as already known). The five other extraction methods (dowex resin, artificial seawater of half salinity and extractions after pretreatment with gluteraldehyde by three methods: water, dowex water and dowex buffer) did not provoke cell lysis as shown by transmission electronic microscopy. This result was confirmed by the minimum release of internal compounds (protein, ATP) and by the low proportions of glucose in dowex-extracted EPS compared with the water-extracted EPS, from which the high glucose content must be inferred as contamination by the chrysolaminaran. The extraction with dowex resin resulted in the second-highest concentration of carbohydrate after the water extraction and the EPS were especially rich in deoxy sugars, hence increasing the hydrophobic feature of these substances. For these reasons, we recommend extraction with dowex, which is also the best method for extracting bound EPS from other biofilms such as in activated sludges.
Myristoylated alanine-rich C kinase substrate (MARCKS), a substrate of protein kinase C (PKC) has been suggested to be implicated in cell adhesion, secretion, and motility through the regulation of the actin cytoskeletal structure. The quantitative real-time-polymerase chain reaction analysis revealed that MARCKS is significantly overexpressed in Opisthorchis viverriniassociated cholangiocarcinoma (CCA) (P = 0.001) in a hamster model, which correlated with the results of mRNA in situ hybridization. An immunohistochemical analysis of 60 CCA patients revealed a significant increase of MARCKS expression. Moreover, the log-rank analysis indicated that CCA patients with a high MARCKS expression have significantly shorter survival times than those with a low MARCKS expression (P = 0.02). This study investigated whether MARCKS overexpression is associated with CCA metastasis. Using a confocal microscopic analysis of CCA cell lines that had been stimulated with the PKC activator, 12-0-tetradecanoyl phorbol-13-acetate (TPA), MARCKS was found to be translocated from the plasma membrane to the perinuclear area. In addition, phosphorylated MARCKS (pMARCKS) became highly concentrated in the perinuclear area. Moreover, an adhesion assay demonstrated that the exogenous overexpression of MARCKS remarkably promoted cell attachment. Interestingly, after TPA stimulation, the CCA cell line-depleted MARCKS showed a decrease in migration and invasion activity. It can be concluded that in non-stimulation, MARCKS promotes cell attachment to the extracellular matrix. After TPA stimulation, PKC phosphorylates MARCKS leading to cell migration or invasion. Taken together, the results of this study reveal a prominent role for MARCKS as one of the key players in the migration of CCA cells and suggest that cycling between MARCKS and pMARCKS can regulate the metastasis of biliary cancer cells. (Cancer Sci 2010; 101: 658-665) C holangiocarcinoma (CCA), the malignant tumor arising from the bile duct epithelium, is the most common cancer in Thailand, especially in the northeast. There is strong epidemiological evidence (1)(2)(3) and experimental studies (4)(5)(6) that support an important etiological role for liver fluke (Opisthorchis viverrini [Ov]) infection in the development of CCA in humans. There is accumulating evidence that Ov infection enhances the risk of CCA via chronic inflammation. (7,8) Recently, Pinlaor et al. (9) suggested that oxidative and nitrosative damage to DNA in the liver of Ov-infected hamsters can play a key role in the modulation of gene expression, which enhances the effect of the DNA adduct and can drive a normal cell undergo tumor development. Additionally, Thanan et al. (10) reported that the highest 8-oxodG level, which is the biomarker of DNA damage, was observed for CCA patients, and a higher level was found in the urine and leukocytes of Ov-infected patients than that in healthy patients.The gene expression profiles of Ov-associated CCA tumors, as investigated by Loilome et al.(11) , indicated that myristoyla...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.