Metabolic oxidative stress activates signal transduction and gene expression during glucose deprivation in human tumor cells

The mechanism of glucose deprivation-induced activation of Lyn kinase (Lyn) , c-Jun N-terminal kinase 1 (JNK1) and increased expression of basic fibrob last growth factor (bFGF) and c-Myc was investigated in MCF-7/ADR adriamyci n-resistant human breast carcinoma cells. Glucose deprivation significantly increased steady state levels of oxidized glutathione content (GSSG) and i ntracellular prooxidants (presumably hydroperoxides) as well as caused the activation of Lyn, JNK1, and the accumulation of bFGF and c-Myc mRNA. The s uppression of GSSG accumulation and prooxidant production by treatment with the thiol antioxidant, N-acetylcysteine, also suppressed all the increases in kinase activation and gene expression observed during glucose deprivati on. In addition, glucose deprivation was shown to induce oxidative stress i n IMR90 SV40 transformed human fibroblasts, indicating that this phenomena- is not limited to the MCF-7/ADR cell line. These and previous observations from our laboratory show that glucose deprivation induced oxidative stress in MCF-7/ADR cells activates signal transduction involving Lyn, JNK1, and m itogen activated protein kinases (ERK1/ERK2) which results in increased bFG F and c-Myc mRNA accumulation. These results provide support for the hypoth esis that alterations in intracellular oxidation/reduction reactions link c hanges in glycolytic metabolism to signal transduction and gene expression in these human tumor cells. (C) 1998 Elsevier Science Inc.