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Cited by 320Sulfur Compounds in BiologyRedox biology and oxidative stressCell death mechanisms and regulation

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Unraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy

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Lv, Huanhuan, Zhen, Chenxiao, Liu, Junyu, Yang, Pengfei, Hu, Lijiang, Shang, Peng·2019·Oxidative Medicine and Cellular Longevity
DOI 10.1155/2019/3150145PMC PMC6590529
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Abstract

Glutathione is the principal intracellular antioxidant buffer against oxidative stress and mainly exists in the forms of reduced glutathione (GSH) and oxidized glutathione (GSSG). The processes of glutathione synthesis, transport, utilization, and metabolism are tightly controlled to maintain intracellular glutathione homeostasis and redox balance. As for cancer cells, they exhibit a greater ROS level than normal cells in order to meet the enhanced metabolism and vicious proliferation; meanwhile, they also have to develop an increased antioxidant defense system to cope with the higher oxidant state. Growing numbers of studies have implicated that altering the glutathione antioxidant system is associated with multiple forms of programmed cell death in cancer cells. In this review, we firstly focus on glutathione homeostasis from the perspectives of glutathione synthesis, distribution, transportation, and metabolism. Then, we discuss the function of glutathione in the antioxidant process. Afterwards, we also summarize the recent advance in the understanding of the mechanism by which glutathione plays a key role in multiple forms of programmed cell death, including apoptosis, necroptosis, ferroptosis, and autophagy. Finally, we highlight the glutathione-targeting therapeutic approaches toward cancers. A comprehensive review on the glutathione homeostasis and the role of glutathione depletion in programmed cell death provide insight into the redox-based research concerning cancer therapeutics.

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Figures

Figure 1 Two-step enzymatic reaction of glutathione synthesis. The first step is the coupling of L-glutamate and cysteine to produce γ-glutamylcysteine under the catalysis of glutamate-cysteine ligase (GCL). The second step is the coupling of γ-glutamylcysteine to glycine catalyzing by glutathione synthetase (GS). Each reaction consumes one ATP molecule. Glutathione exists in the forms of reduced GSH and oxidized GSSG.
Figure 1 Two-step enzymatic reaction of glutathione synthesis. The first step is the coupling of L-glutamate and cysteine to produce γ-glutamylcysteine under the catalysis of glutamate-cysteine ligase (GCL). The second step is the coupling of γ-glutamylcysteine to glycine catalyzing by glutathione synthetase (GS). Each reaction consumes one ATP molecule. Glutathione exists in the forms of reduced GSH and oxidized GSSG.CC BY · PubMed Central
Figure 2 Distribution of intracellular GSH. GSH is distributed in the cytosol, nucleus, mitochondria, and ER.
Figure 2 Distribution of intracellular GSH. GSH is distributed in the cytosol, nucleus, mitochondria, and ER.CC BY · PubMed Central
Figure 3 Transport of GSH. The liver is the main source of GSH, the kidney is the main organ that ingests and degrades GSH, and the small intestine participates in the GSH enterohepatic circulation. The renal proximal tubule is the place where the whole process of GSH transport, synthesis, and degradation is completed.
Figure 3 Transport of GSH. The liver is the main source of GSH, the kidney is the main organ that ingests and degrades GSH, and the small intestine participates in the GSH enterohepatic circulation. The renal proximal tubule is the place where the whole process of GSH transport, synthesis, and degradation is completed.CC BY · PubMed Central
Figure 4 Two degradation pathways of GSH. One way occurs outside the cell where GSH is degraded by γ-glutamyltransferase (GGT) which is expressed only on the outer surface of particular cell; the other newly discovered pathway occurs in the cytoplasm where GSH is degraded through ChaC1 and ChaC2.
Figure 4 Two degradation pathways of GSH. One way occurs outside the cell where GSH is degraded by γ-glutamyltransferase (GGT) which is expressed only on the outer surface of particular cell; the other newly discovered pathway occurs in the cytoplasm where GSH is degraded through ChaC1 and ChaC2.CC BY · PubMed Central
Figure 5 The antioxidant role of cellular GSH. Glutathione peroxidase (GPX) converts H2O2 and Lipid-OOH to H2O and Lipid-OH where GSH is oxidized to GSSG, and glutathione reductase (GR) reduced GSSG to GSH dependent on NADPH, thereby forming a redox cycle to prevent oxidative damage.
Figure 5 The antioxidant role of cellular GSH. Glutathione peroxidase (GPX) converts H2O2 and Lipid-OOH to H2O and Lipid-OH where GSH is oxidized to GSSG, and glutathione reductase (GR) reduced GSSG to GSH dependent on NADPH, thereby forming a redox cycle to prevent oxidative damage.CC BY · PubMed Central
Figure 6 The role of cellular GSH in apoptosis and necroptosis. GSH depletion through nutrition starvation or GSH synthesis inhibition or conjugation with GSH or GSH efflux or GSH degradation induces ROS generation which results in the occurrence of proapoptotic signals, such as the disruption of MMP, increased bax, decreased bcl2, cytochrome c release, and caspase activation. Excess ROS accumulation induces necroptosis.
Figure 6 The role of cellular GSH in apoptosis and necroptosis. GSH depletion through nutrition starvation or GSH synthesis inhibition or conjugation with GSH or GSH efflux or GSH degradation induces ROS generation which results in the occurrence of proapoptotic signals, such as the disruption of MMP, increased bax, decreased bcl2, cytochrome c release, and caspase activation. Excess ROS accumulation induces necroptosis.CC BY · PubMed Central
Figure 7 The mechanism of GSH depletion in induction of ferroptosis. Lipid-OOHs can be formed by autoxidation via Fenton reaction or by enzymatic reaction via lipoxygenases (LOXs). Lipid-OOHs are regulated by the balance between the activities of GPX4 and LOXs or Fenton reaction. System Xc− impairment or GPX4 inactivation leads to Lipid-OOH accumulation which cannot be effectively cleared under the loss of GPX4 activity. Ultimately, the accumulation of Lipid-OOH triggers ferroptosis. Ferroptosis can be inhibited by DFO, liproxstatin-1 (Lip-1), and ferrostatin-1 (Fer-1).
Figure 7 The mechanism of GSH depletion in induction of ferroptosis. Lipid-OOHs can be formed by autoxidation via Fenton reaction or by enzymatic reaction via lipoxygenases (LOXs). Lipid-OOHs are regulated by the balance between the activities of GPX4 and LOXs or Fenton reaction. System Xc− impairment or GPX4 inactivation leads to Lipid-OOH accumulation which cannot be effectively cleared under the loss of GPX4 activity. Ultimately, the accumulation of Lipid-OOH triggers ferroptosis. Ferroptosis can be inhibited by DFO, liproxstatin-1 (Lip-1), and ferrostatin-1 (Fer-1).CC BY · PubMed Central
Figure 8 The role of cellular GSH in autophagy. GSH depletion through nutrition starvation or GSH synthesis inhibition or conjugation with GSH or GSH efflux induces ROS generation. ROS accumulation promotes changes in autophagy-related proteins, such as LC3 I/II conversion, p62 degradation, and autophagic vacuole formation. Additionally, ROS induce NCOA4-mediated ferritin degradation in an autophagy process, called ferritinophagy, which is promoting free iron release and accelerating ROS generation.
Figure 8 The role of cellular GSH in autophagy. GSH depletion through nutrition starvation or GSH synthesis inhibition or conjugation with GSH or GSH efflux induces ROS generation. ROS accumulation promotes changes in autophagy-related proteins, such as LC3 I/II conversion, p62 degradation, and autophagic vacuole formation. Additionally, ROS induce NCOA4-mediated ferritin degradation in an autophagy process, called ferritinophagy, which is promoting free iron release and accelerating ROS generation.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. 2003, Journal of Biological Chemistry, 281, 6372
  2. 2012, Toxicologic Pathology, 29, 997
  3. 2015, Anticancer Research, 35, 677

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Metadata

Authors
Lv, H., Zhen, C., Liu, J., Yang, P., Hu, L., & Shang, P.
Affiliations
  • Northwestern Polytechnical University (CN)
  • Zhejiang Heye Health Technology Co. Ltd., Anji, Zhejiang 313300, China
Corresponding author
Shang, Peng
ORCID
Venue
Oxidative Medicine and Cellular Longevity
Publisher
Wiley
Published
2019-06-10
Volume
2019
Pages
1-16
ISSN
  • 1942-0994 (ISSN-L)
  • 1942-0900
DOI
10.1155/2019/3150145
PMC
PMC6590529
OpenAlex
W2949432489
Cited by
320
References
164
Citations by year
2026: 15 · 2025: 34 · 2024: 78 · 2023: 64 · 2022: 43 · 2021: 46 · 2020: 35 · 2019: 4
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Oxidative Medicine and Cellular Longevity (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Northwestern Polytechnical University Foundation for Fundamental Research (3102018JGC012, 3102017OQD111, 51777171, 11872316, 81803032)
  • Fundamental Research Funds for the Central Universities (3102018JGC012, 3102017OQD111, 51777171, 11872316, 81803032)
  • National Natural Science Foundation of China (3102018JGC012, 3102017OQD111, 51777171, 11872316, 81803032)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
glutathione, glutathione homeostasis, redox homeostasis, oxidative stress, cancer cells, programmed cell death, apoptosis, necroptosis, ferroptosis, autophagy, glutathione depletion, glutathione metabolism
MeSH terms
Glutathione, Humans, Neoplasms, Cell Death

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