Nuclear-factor-κB (NF-κB) and radical oxygen species play contrary roles in transforming growth factor-β1 (TGF-β1)-induced apoptosis in hepatocellular carcinoma (HCC) cells

2008 ◽  
Vol 377 (4) ◽  
pp. 1107-1112 ◽  
Author(s):  
Fang Wang ◽  
Swayamjot Kaur ◽  
Lakita G. Cavin ◽  
Marcello Arsura
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transforming Growth Factor ◽  
Nuclear Factor Κb ◽  
Transforming Growth Factor Β1 ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Radical Oxygen Species ◽  
Induced Apoptosis ◽  
Tgf Β1 ◽  
Hcc Cells

Pyrrolidine dithiocarbamate attenuates paraquat-induced acute pulmonary poisoning in vivo via transforming growth factor β1 and nuclear factor κB pathway interaction

2016 ◽  
Vol 35 (12) ◽  
pp. 1312-1318 ◽  
Author(s):  
M Huang ◽  
D Lou ◽  
H-H Li ◽  
Q Cai ◽  
Y-P Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Nuclear Factor Κb ◽  
Transforming Growth Factor Β1 ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Factor ◽  
Tgf Β1

Paraquat (PQ) exposure could cause pulmonary fibrosis. The aim of this study was to investigate the protective effect of pyrrolidine dithiocarbamate (PDTC) in an acute PQ poison model. One hundred and forty-four Sprague Dawley rats were equally divided into three experimental groups: control group, PQ group, and PQ + PDTC group. At days 1, 3, 7, 14, 28, and 56 of treatment, the serum levels of transforming growth factor β1 (TGF-β1), the levels of hydroxyproline, the protein expression of nuclear factor κB (NF-κB) pathway, and histopathological change in lung tissue were assessed. The survival rate of rats treated with PQ + PDTC was increased compared with that of rats treated only with PQ ( p < 0.05), and the occurrence of pathological changes was dramatically attenuated in the PQ + PDTC group. The serum levels of TGF-β1 and the hydroxyproline levels in the PQ group were significantly increased in a time-dependent manner compared with those in the control and PQ + PDTC groups on days 7, 14, 28, and 56 ( p < 0.05). Additionally, the protein levels of NF-κB proteins p65, inhibitor of κB (IκB) kinase (IKKβ, and IκB-α were significantly downregulated in the PQ + PDTC group as determined by array analysis. The present findings suggest that overexpression of TGF-β1 may play an important role in PQ-induced lung injury and that PDTC, a strong NF-κB inhibitor, can rescue PQ-induced pulmonary fibrosis by influencing the protein expression of NF-κB pathway.

Serotonin 5-HT2A receptor induces TGF-β1 expression in mesangial cells via ERK: proliferative and fibrotic signals

1999 ◽  
Vol 276 (6) ◽  
pp. F922-F930 ◽  
Author(s):  
Jasjit S. Grewal ◽  
Yurii V. Mukhin ◽  
Maria N. Garnovskaya ◽  
John R. Raymond ◽  
Eddie L. Greene
Keyword(s):  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β1 ◽  
Oxygen Species ◽  
Extracellular Signal Regulated Kinase ◽  
Mrna Induction ◽  
Kinase C ◽  
Extracellular Signal ◽  
Signaling Components ◽  
Tgf Β1

We examined the links between fibrotic and proliferative pathways for the 5-HT2A receptor in rat mesangial cells. Serotonin (5-hydroxytryptamine, 5-HT) induced transforming growth factor-β1 (TGF-β1) mRNA in a concentration-dependent (peak at 30 nM 5-HT) and time-dependent fashion. For 10 nM 5-HT, the effect was noticeable at 1 h and maximal by 6 h. Inhibition of 1) protein kinase C (PKC), 2) mitogen- and extracellular signal-regulated kinase kinase (MEK1) with 2′-amino-3′-methoxyflavone (PD-90859), and 3) extracellular signal-regulated kinase (ERK) with apigenin attenuated this effect. The effect was blocked by antioxidants, N-acetyl-l-cysteine (NAC) and α-lipoic acid, and mimicked by direct application of H2O2. TGF-β1 mRNA induction was also blocked by diphenyleneiodonium and 4-(2-aminoethyl)-benzenesulfonyl fluoride, which inhibit NAD(P)H oxidase, a source of oxidants. 5-HT increased the amount of TGF-β1 protein, validating the mRNA studies and demonstrating that 5-HT potently activates ERK and induces TGF-β1 mRNA and protein in mesangial cells. Mapping studies strongly supported relative positions of the components of the signaling cascade as follow: 5-HT2A receptor → PKC → NAD(P)H oxidase/reactive oxygen species → MEK → ERK → TGF-β1 mRNA. These studies demonstrate that mitogenic signaling components (PKC, MEK, and oxidants) are directly linked to the regulation of TGF-β1, a key mediator of fibrosis. Thus a single stimulus can direct both proliferative and fibrotic signals in renal mesangial cells.

scholarly journals Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor κB to modulate tumour necrosis factor-induced apoptosis: evidence from mitochondria-targeted antioxidants

2005 ◽  
Vol 389 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Gillian HUGHES ◽  
Michael P. MURPHY ◽  
Elizabeth C. LEDGERWOOD
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Mitochondrial Matrix ◽  
Mitochondrial Ros ◽  
Induced Apoptosis ◽  
Necrosis Factor

ROS (reactive oxygen species) from mitochondrial and non-mitochondrial sources have been implicated in TNFα (tumour necrosis factor α)-mediated signalling. In the present study, a new class of specific mitochondria-targeted antioxidants were used to explore directly the role of mitochondrial ROS in TNF-induced apoptosis. MitoVit E {[2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethyl]triphenylphosphonium bromide} (vitamin E attached to a lipophilic cation that facilitates accumulation of the antioxidant in the mitochondrial matrix) enhanced TNF-induced apoptosis of U937 cells. In time course analyses, cleavage and activation of caspase 8 in response to TNF were not affected by MitoVit E, whereas the activation of caspase 3 was significantly increased. Furthermore, there was an increased cleavage of the proapoptotic Bcl-2 family member Bid and an increased release of cytochrome c from mitochondria, in cells treated with TNF in the presence of MitoVit E. We considered several mechanisms by which MitoVit E might accelerate TNF-induced apoptosis including mitochondrial integrity (ATP/ADP levels and permeability transition), alterations in calcium homoeostasis and transcription factor activation. Of these, only the transcription factor NF-κB (nuclear factor κB) was implicated. TNF caused maximal nuclear translocation of NF-κB within 15 min, compared with 1 h in cells pretreated with MitoVit E. Thus the accumulation of an antioxidant within the mitochondrial matrix enhances TNF-induced apoptosis by decreasing or delaying the expression of the protective antiapoptotic proteins. These results demonstrate that mitochondrial ROS production is a physiologically relevant component of the TNF signal-transduction pathway during apoptosis, and reveal a novel functional role for mitochondrial ROS as a temporal regulator of NF-κB activation and NF-κB-dependent antiapoptotic signalling.

scholarly journals Smad7 Abrogates Transforming Growth Factor-β1-mediated Growth Inhibition in COLO-357 Cells through Functional Inactivation of the Retinoblastoma Protein

2005 ◽  
Vol 280 (23) ◽  
pp. 21858-21866 ◽  
Author(s):  
Nichole Boyer Arnold ◽  
Murray Korc
Keyword(s):  
Growth Factor ◽  
Growth Inhibition ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Retinoblastoma Protein ◽  
Transforming Growth Factor Β1 ◽  
Type I ◽  
Pancreatic Cancer Cells ◽  
Induced Apoptosis ◽  
Tgf Β1

Smad7 is overexpressed in 50% of human pancreatic cancers. COLO-357 pancreatic cancer cells engineered to overexpress Smad7 are resistant to the actions of transforming growth factor-β1 (TGF-β1) with respect to growth inhibition and cisplatin-induced apoptosis but not with respect to modulation of gene expression. To delineate the mechanisms underlying these divergent consequences of Smad7 overexpression, we studied the effects of Smad7 on TGF-β1-dependent signaling pathways and cell cycle regulating proteins. TGF-β1 induced the phosphorylation of MAPK, p38 MAPK, and AKT2 irrespective of the levels of Smad7, and inhibitors of these pathways did not alter TGF-β1 actions on cell growth. By contrast, Smad7 overexpression interfered with TGF-β1-mediated attenuation of cyclin A and B levels, inhibition of cdc2 dephosphorylation and CDK2 inactivation, up-regulation of p27, and the maintenance of the retinoblastoma protein (RB) in a hypophosphorylated state. Smad7 also suppressed TGF-β1-mediated inhibition of E2F activity but did not alter TGF-β1-mediated phosphorylation of Smad2, the nuclear translocation of Smad2/3/4, or DNA binding of the Smad2/3/4 complex. Although Smad7 did not associate with the type I TGF-β receptor (TβRI), SB-431542, an inhibitor of the kinase activity of this receptor, blocked TGF-β1-mediated effects on Smad-2 phosphorylation. These findings point toward a novel paradigm whereby Smad7 acts to functionally inactivate RB and de-repress E2F without blocking the activation of TβRI and the nuclear translocation of Smad2/3, thereby allowing for TGF-β1 to exert effects in a cancer cell that is resistant to TGF-β1-mediated growth inhibition.

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