Journal
FASEB JOURNAL
Volume 15, Issue 12, Pages 2131-2139Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.01-0131com
Keywords
cellular redox; GSH : GSSG ratio; cell cycle arrest; intestinal cell turnover; EGF
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Funding
- NIDDK NIH HHS [DK 44510, R01 DK044510-08, R01 DK044510] Funding Source: Medline
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Intracellular redox status plays a critical role in cell function, such as proliferation. Oxidative stress, which elicits redox imbalance, also affects cell growth. Therefore, it is often difficult to distinguish the effects of redox imbalance from those of oxidative stress. The objective of this study was to determine the role of redox imbalance independent of reactive oxygen species (ROS) production, in proliferation of human colonic CaCo-2 cells. Low concentrations of diamide plus 1,3-bis(2 chloroethyl)-1-nitrosourea (BCNU) increased intracellular GSSG and decreased GSH and the GSH: GSSG ratio. These changes occurred within 30 min, which preceded a decrease in thymidine incorporation at 6 and 24 h. ROS formation was not detected under these conditions. This suppression of cell proliferative activity was attenuated by N-acetyl cysteine, in parallel with restoration of the intracellular GSH redox status. DL-buthionine-[S, R]-sulfoximine (BSO) decreased intracellular GSH level, but did not change the GSH: GSSG ratio. BSO alone had no effect on cell proliferation, but its presence exaggerated the suppressive effect of diamide plus BCNU. Flow cytometric analysis showed that cells were arrested at G(1)-to-S transition and G(2)/M phase. Collectively, this study shows that mild intracellular redox imbalance inhibited cell proliferation independent of ROS generation. Moreover, cells with compromised cellular GSH were susceptible to redox imbalance-induced inhibition of proliferation.
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