Protective role of Bcl2 in metabolic oxidative stress-induced cell death.
Previous studies have shown that overexpression of Bcl2 protects cells from glucose deprivation-induced cell death in multidrug-resistant human breast carcinoma, MCF-7/ADR cells. In this study, we further investigated the protective role of Bcl2 in glucose deprivation-induced cytotoxicity. Although Bcl2 did not prevent a 3.2-fold increase in the level of hydroperoxide during glucose deprivation, it led to a compartmentalization of hydroperoxide molecules in the mitochondria. It also inhibited glucose deprivation-induced cytochrome c release from the mitochondria. It is possible that overexpression of Bcl2 prevents glucose deprivation-induced ceramide generation, probably by preventing the leakage of hydroperoxide from the mitochondria. We also observed that glucose deprivation induced a sixfold increase in oxidized glutathione content, as well as in thiol precursor content. Overexpression of Bcl2 suppressed an increase in oxidized glutathione content and thiol precursor content. Our results indicate that Bcl2 protects cells from metabolic oxidative stress-induced damage by inhibiting the leakage of hydroperoxide from the mitochondria and subsequently preventing ceramide generation. Preventing ceramide generation inhibits the signal transduction pathway and results in the suppression of cytochrome c release from the mitochondria.
Lee
Y J
YJ
Department of Pharmacology and Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA. Leeyj@msx.upmc.edu
Chen
J C
JC
Amoscato
A A
AA
Bennouna
J
J
Spitz
D R
DR
Suntharalingam
M
M
Rhee
J G
JG
D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002451:Cell Compartmentation; D016923:Cell Death / Q000502:physiology*; D003470:Culture Media; D003574:Cytochrome c Group / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D021241:Spectrometry, Mass, Electrospray Ionization; D014407:Tumor Cells, Cultured
D003470:Culture Media; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D006861:Hydrogen Peroxide; D005978:Glutathione; D005947:Glucose