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

Abstract

MG132 as a proteasome inhibitor can induce apoptotic cell death in lung cancer cells. However, little is known about the toxicological cellular effects of MG132 on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on MG132-treated human pulmonary fibroblast (HPF) cells in relation to cell death, reactive oxygen species (ROS) and glutathione (GSH). MG132 induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm). MG132 increased ROS levels and GSH-depleted cell numbers in HPF cells. Both antioxidants, NAC and vitamin C, prevented growth inhibition, death and MMP (∆ψm) loss in MG132-treated HPF cells and also attenuated ROS levels in these cells. BSO showed a strong increase in ROS levels in MG132-treated HPF cells and slightly enhanced the growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion. In addition, NAC decreased anonymous ubiquitinated protein levels in MG132-treated HPF cells. Furthermore, superoxide dismutase (SOD) 2, catalase (CTX) and GSH peroxidase (GPX) siRNAs enhanced HPF cell death by MG132, which was not correlated with ROS and GSH level changes. In conclusion, MG132 induced the growth inhibition and death of HPF cells, which were accompanied by increasing ROS levels and GSH depletion. Both NAC and vitamin C attenuated HPF cell death by MG132, whereas BSO slightly enhanced the death.

• Authors: Woo Hyun Park, Suhn Hee Kim
• Journal: Oncology reports (Oncol Rep) Vol. 27 Issue 4 Pg. 1284-91 (Apr 2012) ISSN: 1791-2431 [Electronic] Greece
• PMID: 22266922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Leupeptins
• Protease Inhibitors
• Proteasome Inhibitors
• Reactive Oxygen Species
• Catalase
• Glutathione Peroxidase
• Superoxide Dismutase
• superoxide dismutase 2
• Proteasome Endopeptidase Complex
• Glutamate-Cysteine Ligase
• Glutathione
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Antioxidants (pharmacology)
• Catalase (genetics, metabolism)
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Down-Regulation
• Fibroblasts (drug effects, enzymology, pathology)
• Glutamate-Cysteine Ligase (antagonists & inhibitors, metabolism)
• Glutathione (metabolism)
• Glutathione Peroxidase (genetics, metabolism)
• Humans
• Leupeptins (pharmacology)
• Lung (drug effects, enzymology, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Oxidative Stress (drug effects)
• Protease Inhibitors (pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors
• RNA Interference
• Reactive Oxygen Species (metabolism)
• Superoxide Dismutase (genetics, metabolism)
• Transfection
• Ubiquitination
• Up-Regulation