Transforming growth factor-beta1 (TGF-beta1) plays a crucial role in adhesion and migration of human cancer cells. Besides, integrins are the major adhesive molecules in mammalian cells. Here we found that TGF-beta1 increased the migration and cell surface expression of beta1 integrin in human lung cancer cells (A549 cells). TGF-beta1 stimulation increased phosphorylation of p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) and Ser(473) of Akt was determined. Besides, we performed that PI3K inhibitor (Ly294002) or Akt inhibitor suppressed the TGF-beta1-induced migration activities of A549 cells. Treatment of A549 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also repressed TGF-beta1-induced cells migration and beta1 integrins expression. In addition, treatment of A549 cells with TGF-beta1 induced IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the TGF-beta1-mediated increases in IKKalpha/beta, IkappaBalpha phosphorylation and p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Co-transfection with p85alpha and Akt mutants also reduced the TGF-beta1-induced kappaB-luciferase activity. Taken together, our results suggest that TGF-beta1 acts through PI3K/Akt, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of beta1 integrins and contributing the migration of human lung cancer cells.
"The most well-characterized factor responsible for induction of EMT by far is TGF-β, which is a multifunctional cytokine and is involved in many biological processes including cell proliferation, differentiation and migration (Lawrence, 1996; Zhang, 2011). Three members of TGFβ have been identified, namely TGF-β1, 2, and 3, and TGF-β1 is proved to be highly correlated with EMT (Dalal et al., 1993; Fong et al., 2009). Some molecules including Smad, RhoA, Rac1, Ras and MAPK were reported to be involved in TGF-β1-triggered EMT (Janda et al., 2002; Huang et al., 2004; Zavadil et al., 2004; Willis and Borok, 2007). "
[Show abstract][Hide abstract] ABSTRACT: Luteolin is a natural flavonoid that possesses a variety of pharmacological activities, such as anti-inflammatory and anti-cancer abilities. Whether luteolin regulates the transformation ability of Lung cancer cells remains unclear. The current study aims to uncover the effects and underling mechanisms of luteolin in regulation of and Epithelial-mesenchymal transition of lung cancer cells.
The lung adenocarcinoma A549 cells were used in this experiment; the cells were pretreated with luteolin followed by administration with TGF-β1. The expression levels of various cadherin and related upstream regulatory modules were examined, KEY FINDINGS: Pretreatment of luteolin prevented the morphological change and downregulation of E-cadherin of A549 cells induced by TGF-β1. In addition, the activation of PI3K-AKT-IκBa-NF-κB-snail pathway which leading to the decline of E-cadherin induced by TGF-β1 also attenuated under the pretreatment of luteolin.
We provide the mechanisms about how luteolin attenuated the Epithelial-mesenchymal transition of A549 lung cancer cells induced by TGF-β1. This finding will strengthen the anti-cancer effects of flavonoid compounds via the regulation of migration/invasion and EMT ability of various cancer cells.
Life sciences 10/2013; 109(2). DOI:10.1016/j.lfs.2013.10.004 · 2.70 Impact Factor
"Integrins exist as hetero dimers of two distinct transmembrane glycoprotein chains, called α and β subunits, that are non-covalently linked. The integrin family consists of 24 different αβ heterodimers
. The binding of an integrin receptor to its extracellular ligand causes a signal to be relayed into the cell, resulting in the regulation of specific gene expression
[Show abstract][Hide abstract] ABSTRACT: Seaweeds are commonly used as functional foods and drugs. A glycoprotein (GP) from the green alga Capsosiphon fulvescens (Cf) has been reported to have antitumor activity toward various cancer cells. We previously observed that Cf-GP induced different pathways of apoptosis in AGS human gastric cancer cells. Transforming growth factor (TGF)-β1 plays an important role in cancer cell migration. Increased TGF-β1 levels increase the expression of the small GTPases and activate the FAK/PI3K/AKT pathways, resulting in the upregulation of integrin receptor proteins, which mediate the attachment of cells to surrounding tissues, cells or extracellular matrix. Thus, the inhibition of TGF-β1 signaling would downregulate integrin expression and thereby effectively decrease cell growth and migration. In the present study, we determined the effect of Cf-GP treatment on the proliferation, migration and apoptosis of AGS human gastric cancer cells. To investigate the mechanism by which Cf-GP exerts its anticancer actions, we examined the effect of Cf-GP on the expression levels of TGF-β1, FAK, PI3K, AKT, the small GTPases and integrins in AGS cells. Our findings indicate that Cf-GP inhibits AGS cell proliferation and migration by downregulating integrin expression via the TGF-β1-activated FAK/PI3K/AKT pathways. These results suggest that Cf-GP may be an important factor in the development of functional foods and therapeutic agents.
International Journal of Oncology 08/2013; 43(4). DOI:10.3892/ijo.2013.2055 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vanillin, a food flavoring agent, has been shown to suppress cancer cell migration and metastasis in a mouse model, but its mechanism of action is unknown. In this report, we have examined the antimetastatic potential of vanillin and its structurally related compounds, vanillic acid, vanillyl alcohol, and apocynin on hepatocyte growth factor (HGF)-induced migration of human lung cancer cells by the Transwell assay. Vanillin and apocynin could inhibit cell migration, and both compounds selectively inhibited Akt phosphorylation of HGF signaling, without affecting phosphorylation of Met and Erk. Vanillin and apocynin could inhibit the enzymatic activity of phosphoinositide 3-kinase (PI3K), as revealed by an in vitro lipid kinase assay, suggesting that inhibition of PI3K activity was a mechanism underlying the inhibitory effect on cancer cell migration, and the presence of an aldehyde or ketone group in the vanillin structure was important for this inhibition. Vanillin and apocynin also inhibited angiogenesis, determined by the chick chorioallantoic membrane assay.
Journal of Agricultural and Food Chemistry 05/2009; 57(8):3055-63. DOI:10.1021/jf803366f · 2.91 Impact Factor
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