TY - JOUR
T1 - Mitochondrial O2.- and H2O2 mediate glucose deprivation-induced cytotoxicity and oxidative stress in human cancer cells
AU - Ahmad, Iman M.
AU - Aykin-Burns, Nukhet
AU - Sim, Julia E.
AU - Walsh, Susan A.
AU - Higashikubo, Ryuji
AU - Buettner, Garry R.
AU - Venkataraman, Sujatha
AU - Mackey, Michael A.
AU - Flanagan, Shawn W.
AU - Oberley, Larry W.
AU - Spitz, Douglas R.
PY - 2005/2/11
Y1 - 2005/2/11
N2 - The hypothesis that glucose deprivation-induced cytotoxicity in transformed human cells is mediated by mitochondrial O2.- and H 2O2 was first tested by exposing glucose-deprived SV40-transformed human fibroblasts (GM00637G) to electron transport chain blockers (ETCBs) known to increase mitochondrial O2.- and H2O2 production (antimycin A (AntA), myxothiazol (Myx), or rotenone (Rot)). Glucose deprivation (2-8 h) in the presence of ETCBs enhanced parameters indicative of oxidative stress (i.e. GSSG and steady-state levels of oxygen-centered radicals) as well as cytotoxicity. Glucose deprivation in the presence of AntA also significantly enhanced cytotoxicity and parameters indicative of oxidative stress in several different human cancer cell lines (PC-3, DU145, MDA-MB231, and HT-29). In addition, human osteosarcoma cells lacking functional mitochondrial electron transport chains (rho(0)) were resistant to glucose deprivation-induced cytotoxicity and oxidative stress in the presence of AntA. In the absence of ETCBs, aminotriazole-mediated inactivation of catalase in PC-3 cells demonstrated increases in intracellular steady-state levels of H2O2 during glucose deprivation. Finally, in the absence of ETCBs, overexpression of manganese containing superoxide dismutase and/or mitochondrial targeted catalase using adenoviral vectors significantly protected PC-3 cells from toxicity and oxidative stress induced by glucose deprivation with expression of both enzymes providing greater protection than was seen with either alone. Overall, these findings strongly support the hypothesis that mitochondrial O2.- and H 2O2 significantly contribute to glucose deprivation-induced cytotoxicity and metabolic oxidative stress in human cancer cells.
AB - The hypothesis that glucose deprivation-induced cytotoxicity in transformed human cells is mediated by mitochondrial O2.- and H 2O2 was first tested by exposing glucose-deprived SV40-transformed human fibroblasts (GM00637G) to electron transport chain blockers (ETCBs) known to increase mitochondrial O2.- and H2O2 production (antimycin A (AntA), myxothiazol (Myx), or rotenone (Rot)). Glucose deprivation (2-8 h) in the presence of ETCBs enhanced parameters indicative of oxidative stress (i.e. GSSG and steady-state levels of oxygen-centered radicals) as well as cytotoxicity. Glucose deprivation in the presence of AntA also significantly enhanced cytotoxicity and parameters indicative of oxidative stress in several different human cancer cell lines (PC-3, DU145, MDA-MB231, and HT-29). In addition, human osteosarcoma cells lacking functional mitochondrial electron transport chains (rho(0)) were resistant to glucose deprivation-induced cytotoxicity and oxidative stress in the presence of AntA. In the absence of ETCBs, aminotriazole-mediated inactivation of catalase in PC-3 cells demonstrated increases in intracellular steady-state levels of H2O2 during glucose deprivation. Finally, in the absence of ETCBs, overexpression of manganese containing superoxide dismutase and/or mitochondrial targeted catalase using adenoviral vectors significantly protected PC-3 cells from toxicity and oxidative stress induced by glucose deprivation with expression of both enzymes providing greater protection than was seen with either alone. Overall, these findings strongly support the hypothesis that mitochondrial O2.- and H 2O2 significantly contribute to glucose deprivation-induced cytotoxicity and metabolic oxidative stress in human cancer cells.
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U2 - 10.1074/jbc.M411662200
DO - 10.1074/jbc.M411662200
M3 - Article
C2 - 15561720
AN - SCOPUS:20044361991
SN - 0021-9258
VL - 280
SP - 4254
EP - 4263
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -