Glucose-6-phosphate dehydrogenase-deficient cells show an increased propensity for oxidant-induced senescence

被引:53
作者
Cheng, ML
Ho, HY
Wu, YH
Chiu, DTY
机构
[1] Chang Gung Univ, Grad Inst Med Biotechnol, Tao Yuan, Taiwan
[2] Chang Gung Univ, Dept Med Biotechnol & Lab Sci, Tao Yuan, Taiwan
[3] Chang Gung Mem Hosp, Dept Clin Pathol, Tao Yuan, Taiwan
[4] Chang Gung Univ, Grad Inst Basic Med Sci, Tao Yuan, Taiwan
关键词
glucose-6-phosphate dehydrogenase; cell growth; cell senescence; NADP(+); NADPH; 8-OHdG; oxidative stress; free radicals;
D O I
10.1016/j.freeradbiomed.2003.11.031
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glucose-6-phosphate dehydrogenase (G6PD) is involved in the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and the maintenance of cellular redox balance. We previously showed that G6PD-deficient fibroblasts undergo growth retardation and premature cellular senescence. In the present study, we demonstrate abatement of both the intracellular G6PD activity and the ratio NADPH/NADP(+) during the serial passage of G6PD-deficient cells. This was accompanied by a significant increase in the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). This suggests that the lowered resistance to oxidative stress and accumulative oxidative damage may account for the premature senescence of these cells. Consistent with this, the G6PD-deficient cells had an increased propensity for hydrogen peroxide (H2O2)-induced senescence; these cells exhibited such senescent phenotypes as large, flattened morphology and increased senescence-associated beta-galactosidase (SA-beta-Gal) staining. Decreases in both the intracellular G6PD, activity and the NADPH/NADP+ ratio were concomitant with an increase in 8-OHdG level in H2O2-induced senescent cells. Exogenous expression of G6PD protected the deficient cells from stress-induced senescence. No significant telomere shortening occurred upon repetitive treatment with H2O2. Simultaneous induction of p16(INK4a) and p53 was detected in G6PD-deficient but not in normal fibroblasts during H2O2-induced senescence. Our findings support the notion that G6PD status, and thus proper redox balance, is a determinant of cellular senescence. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:580 / 591
页数:12
相关论文
共 54 条
[1]   Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts [J].
Alcorta, DA ;
Xiong, Y ;
Phelps, D ;
Hannon, G ;
Beach, D ;
Barrett, JC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (24) :13742-13747
[2]   PURIFICATION AND PROPERTIES OF HUMAN GLUCOSE-6-PHOSPHATE-DEHYDROGENASE MADE IN ESCHERICHIA-COLI [J].
BAUTISTA, JM ;
MASON, PJ ;
LUZZATTO, L .
BIOCHIMICA ET BIOPHYSICA ACTA, 1992, 1119 (01) :74-80
[3]  
Beckman K.B., 1997, OXIDATIVE STRESS MOL, P201
[4]  
BEUTLER E, 1990, SEMIN HEMATOL, V27, P137
[5]  
BEUTLER E, 1991, NEW ENGL J MED, V324, P169
[6]   Telomere states and cell fates [J].
Blackburn, EH .
NATURE, 2000, 408 (6808) :53-56
[7]   Genotoxic lipid peroxidation products: their DNA damaging properties and role in formation of endogenous DNA adducts [J].
Burcham, PC .
MUTAGENESIS, 1998, 13 (03) :287-305
[8]   Cellular senescence in telomerase-expressing Syrian hamster embryo cells [J].
Carman, TA ;
Afshar, CA ;
Barrett, JC .
EXPERIMENTAL CELL RESEARCH, 1998, 244 (01) :33-42
[9]   OXIDATIVE DNA-DAMAGE AND SENESCENCE OF HUMAN-DIPLOID FIBROBLAST CELLS [J].
CHEN, Q ;
FISCHER, A ;
REAGAN, JD ;
YAN, LJ ;
AMES, BN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (10) :4337-4341
[10]   SENESCENCE-LIKE GROWTH ARREST INDUCED BY HYDROGEN-PEROXIDE IN HUMAN-DIPLOID FIBROBLAST F65 CELLS [J].
CHEN, Q ;
AMES, BN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4130-4134