Treatment with p38 inhibitor partially prevents Calu-6 lung cancer cell death by a proteasome inhibitor, MG132.
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.
Han
Yong Hwan
YH
Department of Physiology, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeon Ju, 561-180, Republic of Korea.
Park
Woo Hyun
WH
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*
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