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 fibroblast growth factor (bFGF) and c-Myc was investigated in MCF-7/ADR adriamycin-resistant human breast carcinoma cells. Glucose deprivation significantly increased steady state levels of oxidized glutathione content (GSSG) and intracellular prooxidants (presumably hydroperoxides) as well as caused the activation of Lyn, JNK1, and the accumulation of bFGF and c-Myc mRNA. The suppression 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 deprivation. In addition, glucose deprivation was shown to induce oxidative stress in 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 mitogen activated protein kinases (ERK1/ERK2) which results in increased bFGF and c-Myc mRNA accumulation. These results provide support for the hypothesis that alterations in intracellular oxidation/reduction reactions link changes in glycolytic metabolism to signal transduction and gene expression in these human tumor cells.
Blackburn
R V
RV
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Spitz
D R
DR
Liu
X
X
Galoforo
S S
SS
Sim
J E
JE
Ridnour
L A
LA
Chen
J C
JC
Davis
B H
BH
Corry
P M
PM
Lee
Y J
YJ
D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D005947:Glucose