scholarly journals MG132, a proteasome inhibitor, induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion

2012 ◽  
Vol 27 (4) ◽  
pp. 1284-1291 ◽  
Author(s):  
WOO HYUN PARK ◽  
SUHN HEE KIM
Keyword(s):  
Cell Death ◽  
Proteasome Inhibitor ◽  
Fibroblast Cell ◽  
Pulmonary Fibroblast

Enhancement of gallic acid-induced human pulmonary fibroblast cell death by N-acetyl cysteine and L-buthionine sulfoximine

2010 ◽  
Vol 30 (8) ◽  
pp. 992-999 ◽  
Author(s):  
Bo Ra You ◽  
Woo Hyun Park
Keyword(s):  
Cell Death ◽  
Growth Inhibition ◽  
Gallic Acid ◽  
Buthionine Sulfoximine ◽  
Fibroblast Cell ◽  
Biological Properties ◽  
Dependent Manner ◽  
Toxicological Effect ◽  
Acetyl Cysteine ◽  
Pulmonary Fibroblast

Gallic acid (GA) has various biological properties including anti-cancer effect. However, little is known about the toxicological effect of GA in primary normal cells. Here, we evaluated the effects of GA on human pulmonary fibroblast (HPF) cells in relation to reactive oxygen species (ROS) and glutathione (GSH). GA inhibited the growth of HPF cells at 24 hours in a dose-dependent manner. GA also induced HPF cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; ΔΨm). GA increased ROS levels including O2•- and GSH-depleted cell numbers in HPF cells at 24 hours. Treatment with 2 mM N-acetyl-cysteine (NAC) intensified growth inhibition and death in GA-treated HPF cells. NAC decreased ROS levels and increased GSH depletion in these cells. Treatment with 10 μM L-buthionine sulfoximine (BSO) also enhanced growth inhibition and death in GA-treated HPF cells. BSO increased ROS levels and GSH depletion in these cells. In conclusion, GA-induced HPF cell death was accompanied by ROS increase and GSH depletion. The changes of ROS and GSH levels by NAC and BSO appeared to affect cell growth and death in GA-treated HPF cells.

Mitogen-activated protein kinase inhibitors differently affect the growth inhibition and death of a proteasome inhibitor, MG132-treated human pulmonary fibroblast cells

2011 ◽  
Vol 30 (12) ◽  
pp. 1945-1954 ◽  
Author(s):  
Woo Hyun Park
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Proteasome Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Cell Growth Inhibition ◽  
P38 Inhibitor ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors ◽  
Pulmonary Fibroblast

Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor can induce growth inhibition and death in lung cancer or normal cells. However, little is known about relationship between proteasome inhibition and mitogen-activated protein kinase (MAPK) signaling in normal lung cells. Thus, in the present study, we investigated the effects of MAPK inhibitors on MG132-treated human pulmonary fibroblast (HPF) cells in relation to cell growth inhibition, cell death, reactive oxygen species (ROS) and glutathione (GSH). Treatment with 15 μM MG132 increased ROS levels including mitochondrial O2•− and GSH depleted cell numbers in HPF cells at 24 hours. MAP kinase or ERK kinase (MEK) inhibitor did not significantly affect cell growth inhibition, cell death, the loss of mitochondrial membrane potential (MMP; Δ Ψm), ROS level and GSH depletion in MG132-treated HPF cells. c-Jun N-terminal kinase (JNK) inhibitor attenuated the growth inhibition and death by MG132. This inhibitor also significantly decreased O2•− level in MG132-treated HPF cells. Although p38 inhibitor slightly enhanced HPF cell growth inhibition by MG132, this inhibitor and siRNA prevented HPF cell death induced by MG132. p38 inhibitor also attenuated d O2•− level and GSH depletion. Moreover, extracellular signal regulated kinase (ERK), JNK or p38 siRNA did not strongly affect ROS levels in MG132-treated HPF cells. ERK and JNK siRNAs decreased anonymous ubiquitinated protein levels in MG132-treated HPF cells. In conclusion, MAPK inhibitors differently affected the growth inhibition and death of MG132-treated HPF cells. Especially, p38 inhibitor attenuated HPF cell death by MG132, which was in part related to changes in ROS and GSH levels.

scholarly journals Inhibition of Replication Induces Non-Apoptotic Cell Death in Fibroblast Cell Lines Derived from LEC Rats

2003 ◽  
Vol 65 (2) ◽  
pp. 249-254 ◽  
Author(s):  
Masanobu HAYASHI ◽  
Taku HAMASU ◽  
Daiji ENDOH ◽  
Reiko SHIMOJIMA ◽  
Toyo OKUI
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Fibroblast Cell ◽  
Apoptotic Cell Death ◽  
Lec Rats ◽  
Fibroblast Cell Lines

scholarly journals Yersinia enterocolitica Impairs Activation of Transcription Factor NF-κB: Involvement in the Induction of Programmed Cell Death and in the Suppression of the Macrophage Tumor Necrosis Factor α Production

1998 ◽  
Vol 187 (7) ◽  
pp. 1069-1079 ◽  
Author(s):  
Klaus Ruckdeschel ◽  
Suzanne Harb ◽  
Andreas Roggenkamp ◽  
Mathias Hornef ◽  
Robert Zumbihl ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Tumor Necrosis Factor ◽  
Programmed Cell Death ◽  
Proteasome Inhibitor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

In this study, we investigated the activity of transcription factor NF-κB in macrophages infected with Yersinia enterocolitica. Although triggering initially a weak NF-κB signal, Y. enterocolitica inhibited NF-κB activation in murine J774A.1 and peritoneal macrophages within 60 to 90 min. Simultaneously, Y. enterocolitica prevented prolonged degradation of the inhibitory proteins IκB-α and IκB-β observed by treatment with lipopolysaccharide (LPS) or nonvirulent, plasmid-cured yersiniae. Analysis of different Y. enterocolitica mutants revealed a striking correlation between the abilities of these strains to inhibit NF-κB and to suppress the tumor necrosis factor α (TNF-α) production as well as to trigger macrophage apoptosis. When NF-κB activation was prevented by the proteasome inhibitor MG-132, nonvirulent yersiniae as well as LPS became able to trigger J774A.1 cell apoptosis and inhibition of the TNF-α secretion. Y. enterocolitica also impaired the activity of NF-κB in epithelial HeLa cells. Although neither Y. enterocolitica nor TNF-α could induce HeLa cell apoptosis alone, TNF-α provoked apoptosis when activation of NF-κB was inhibited by Yersinia infection or by the proteasome inhibitor MG-132. Together, these data demonstrate that Y. enterocolitica suppresses cellular activation of NF-κB, which inhibits TNF-α release and triggers apoptosis in macrophages. Our results also suggest that Yersinia infection confers susceptibility to programmed cell death to other cell types, provided that the appropriate death signal is delivered.

scholarly journals Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Jessica Tsalikis ◽  
Mena Abdel-Nour ◽  
Armin Farahvash ◽  
Matthew T. Sorbara ◽  
Stephanie Poon ◽  
...  
Keyword(s):  
Cell Death ◽  
Proteasome Inhibitor ◽  
Adaptor Protein ◽  
Proteasome Inhibition ◽  
20S Proteasome ◽  
Protein Homeostasis ◽  
Cancer Cell Death ◽  
Protein Clearance ◽  
Lysosome Biogenesis

ABSTRACTProtein degradation pathways are critical for maintaining proper protein dynamics within the cell, and considerable efforts have been made toward the development of therapeutics targeting these catabolic processes. We report here that isoginkgetin, a naturally derived biflavonoid, sensitized cells undergoing nutrient starvation to apoptosis, induced lysosomal stress, and activated the lysosome biogenesis geneTFEB. Isoginkgetin treatment led to the accumulation of aggregates of polyubiquitinated proteins that colocalized strongly with the adaptor protein p62, the 20S proteasome, and the endoplasmic reticulum-associated degradation (ERAD) protein UFD1L. Isoginkgetin directly inhibited the chymotrypsin-like, trypsin-like, and caspase-like activities of the 20S proteasome and impaired NF-κB signaling, suggesting that the molecule may display its biological activity in part through proteasome inhibition. Importantly, isoginkgetin was effective at killing multiple myeloma (MM) cell linesin vitroand displayed a higher rate of cell death induction than the clinically approved proteasome inhibitor bortezomib. We propose that isoginkgetin disturbs protein homeostasis, leading to an excess of protein cargo that places a burden on the lysosomes/autophagic machinery, eventually leading to cancer cell death.

MG132 as a proteasome inhibitor induces cell growth inhibition and cell death in A549 lung cancer cells via influencing reactive oxygen species and GSH level

2010 ◽  
Vol 29 (7) ◽  
pp. 607-614 ◽  
Author(s):  
Yong Hwan Han ◽  
Woo Hyun Park
Keyword(s):  
Lung Cancer ◽  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Oxygen Species ◽  
A549 Lung

Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In the present study, we evaluated the effects of MG132 on the growth of A549 lung cancer cells in relation to cell growth, ROS and glutathione (GSH) levels. Treatment with MG132 inhibited the growth of A549 cells with an IC50 of approximately 20 μM at 24 hours. DNA flow cytometric analysis indicated that 0.5 ∼ 30 μM MG132 induced a G1 phase arrest of the cell cycle in A549 cells. Treatment with 10 or 30 μM MG132 also induced apoptosis, as evidenced by sub-G1 cells and annexin V staining cells. This was accompanied by the loss of mitochondrial membrane potential (MMP; Δψm). The intracellular ROS levels including O2•- were strongly increased in 10 or 30 μM MG132-treated A549 cells but were down-regulated in 0.1, 0.5 or 1 μM MG132-treated cells. Furthermore, 10 or 30 μM MG132 increased mitochondrial O2•- level but 0.1, 0.5 or 1 μM MG132 decreased that. In addition, 10 or 30 μM MG132 induced GSH depletion in A549 cells. In conclusion, MG132 inhibited the growth of human A549 cells via inducing the cell cycle arrest as well as triggering apoptosis, which was in part correlated with the changes of ROS and GSH levels. Our present data provide important information on the anti-growth mechanisms of MG132 in A549 lung cancer cells in relation to ROS and GSH.

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