Sedoheptulose-1,7-bisphospate Accumulation and Metabolic Anomalies in Hepatoma Cells Exposed to Oxidative Stress.

Mei-Ling Cheng,Jui-Fen Lin,Cheng-Yu Huang,Guan-Jie Li,Lu-Min Shih,Hung-Yao Ho,Daniel Tsun-Yee Chiu

doi:10.1155/2019/5913635

Mei-Ling Cheng, Jui-Fen Lin + Show 5 more

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https://doi.org/10.1155/2019/5913635

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Abstract

We have previously shown that GSH depletion alters global metabolism of cells. In the present study, we applied a metabolomic approach for studying the early changes in metabolism in hydrogen peroxide- (H2O2-) treated hepatoma cells which were destined to die. Levels of fructose 1,6-bisphosphate and an unusual metabolite, sedoheptulose 1,7-bisphosphate (S-1,7-BP), were elevated in hepatoma Hep G2 cells. Deficiency in G6PD activity significantly reduced S-1,7-BP formation, suggesting that S-1,7-BP is formed in the pentose phosphate pathway as a response to oxidative stress. Additionally, H2O2 treatment significantly increased the level of nicotinamide adenine dinucleotide phosphate (NADP+) and reduced the levels of ATP and NAD+. Severe depletion of ATP and NAD+ in H2O2-treated Hep G2 cells was associated with cell death. Inhibition of PARP-mediated NAD+ depletion partially protected cells from death. Comparison of metabolite profiles of G6PD-deficient cells and their normal counterparts revealed that changes in GSH and GSSG per se do not cause cell death. These findings suggest that the failure of hepatoma cells to maintain energy metabolism in the midst of oxidative stress may cause cell death.

Highlights

Reactive oxygen species (ROS) are implicated in a number of physiological and pathophysiological processes
We examined the changes in the metabolite profile of Hep G2 cells in response to H2O2 treatment
The orthogonal partial least squares discriminate analysis (OPLS-DA) plot showed that the metabolite profile of cells treated with 5 mM H2O2 was significantly different from that of control cells

Summary

Introduction

Reactive oxygen species (ROS) are implicated in a number of physiological and pathophysiological processes. Depending on their level, ROS can serve as signaling molecules to promote cell proliferation or as mediator of cell death. Exposure to relatively high levels of oxidant induces apoptosis and necrosis. Glutathione peroxidase catalyzes reduction of hydroperoxides, accompanied by oxidation of GSH to its disulfide form. The latter is reduced back to GSH through the activity of glutathione reductase. Inefficient NADPH production and GSH regeneration are known to promote death of cells under oxidative stress [5]

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