title: 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.affiliation: Department of Physiology, Medical School, Chonbuk National University, Jeonju 561-180, Republic of Korea. parkwh71@chonbuk.ac.kr
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Park
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D054875:Ubiquitination; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D002374:Catalase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005979:Glutathione Peroxidase; D007976:Leupeptins; D011480:Protease Inhibitors; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde