title: Treatment with p38 inhibitor partially prevents Calu-6 lung cancer cell death by a proteasome inhibitor, MG132.
abstract: MG132 (carbobenzoxy-Leu-Leu-leucinal) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, we investigated the effects of MEK (mitogen-activated protein [MAP] kinase or extracellular signal-regulated kinase [ERK] kinase) or p38 inhibitor on MG132-treated Calu-6 lung cancer cells in relation to cell growth, cell death, ROS, and glutathione (GSH) levels. Treatment with 10 mumol/L MG132 inhibited the growth of Calu-6 cells at 24 hours. MG132 induced apoptosis in Calu-6 cells, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). ROS were increased in MG132-treated Calu-6 cells. MG132 also induced GSH depletion in Calu-6 cells. Treatment with MEK inhibitor did not significantly affect cell growth, cell death, ROS, and GSH levels in MG132-treated Calu-6 cells. Furthermore, MG132 increased the phosphorylation of p38 in Calu-6 cells at 1 and 24 hours. Treatment with p38 inhibitor significantly prevented cell growth inhibition, MMP (DeltaPsi(m)) loss and apoptosis in MG132-treated Calu-6 cells. This inhibitor increased ROS level and decreased GSH depletion in these cells. In conclusion, p38 inhibitor partially prevented Calu-6 cell death by MG132, which might be affected by GSH level changes.
authors.affiliation: Department of Physiology, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Yong Hwan
authors.initials: YH
authors.lastname: Han
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Park
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D005419:Flavonoids / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007976:Leupeptins / Q000633:toxicity*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007976:Leupeptins; D011725:Pyridines; D017382:Reactive Oxygen Species; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; C093642:SB 203580; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one