Abstract
We previously observed that glucose deprivation induces cell death in multidrug-resistant human breast carcinoma cells (MCF-7/ADR). As a follow up we wished to test the hypothesis that metabolic oxidative stress was the causative process or at least the link between causative processes behind the cytotoxicity. In the studies described here, we demonstrate that mitogen-activated protein kinase (MAPK) was activated within 3 min of being in glucose-free medium and remained activated for 3 h. Glucose deprivation for 2-4 h also caused oxidative stress as evidenced by a 3-fold greater steady state concentration of oxidized glutathione and a 3-fold increase in pro-oxidant production. Glucose and glutamate treatment rapidly suppressed MAPK activation and rescued cells from cytotoxicity. Glutamate and the peroxide scavenger, pyruvate, rescued the cells from cell killing as well as suppressed pro-oxidant production. In addition the thiol antioxidant, N-acetyl-L-cysteine, rescued cells from glucose deprivation-induced cytotoxicity and suppressed MAPK activation. These results suggest that glucose deprivation-induced cytotoxicity and alterations in MAPK signal transduction are mediated by oxidative stress in MCF-7/ADR. These results also support the speculation that a common mechanism of glucose deprivation-induced cytotoxicity in mammalian cells may involve metabolic oxidative stress.
Highlights
We have previously observed that glucose deprivation activates mitogen-activated protein kinase (MAPK)1 and induces cell death in multidrug-resistant human breast carcinoma MCF-7/ADR cells [1, 2]
We demonstrate that glucose deprivationinduced cell death in MCF-7/ADR is accompanied by activation of the MAPK pathway as well as oxidative stress as evidenced by significant increases in intracellular oxidized glutathione content and pro-oxidant production
These results indicate that treatment with a thiol antioxidant was capable of inhibiting both the cytotoxicity and the alterations in MAPK signal transduction induced by glucose deprivation in the MCF-7/ADR cells
Summary
We have previously observed that glucose deprivation activates mitogen-activated protein kinase (MAPK) and induces cell death in multidrug-resistant human breast carcinoma MCF-7/ADR cells [1, 2]. Since mitochondrial metabolism would be the preferred route of energy production during glucose deprivation, it is reasonable to hypothesize that glucose deprivation would create a metabolic state where superoxide and hydroperoxide concentrations were increased and peroxide scavenging via pyruvate as well as NADPH-dependent reactions was decreased. This would be expected to result in a condition of metabolic oxidative stress characterized by increased levels of pro-oxidant production and increased levels of oxidized glutathione
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