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: Yong Hwan Han, Woo Hyun Park
• Journal: Cancer genetics and cytogenetics (Cancer Genet Cytogenet) Vol. 199 Issue 2 Pg. 81-8 (Jun 2010) ISSN: 1873-4456 [Electronic] United States
• PMID: 20471510 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Cysteine Proteinase Inhibitors
• Flavonoids
• Imidazoles
• Leupeptins
• Pyridines
• Reactive Oxygen Species
• Calcium-Calmodulin-Dependent Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Glutathione
• SB 203580
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Apoptosis (drug effects)
• Blotting, Western
• Calcium-Calmodulin-Dependent Protein Kinases (antagonists & inhibitors, pharmacology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cysteine Proteinase Inhibitors (toxicity)
• Flavonoids (pharmacology)
• Glutathione (metabolism)
• Humans
• Imidazoles (therapeutic use)
• Leupeptins (toxicity)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Pyridines (therapeutic use)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)