Omega Class Glutathione S‐Transferase: Antioxidant Enzyme in Pathogenesis of Neurodegenerative Diseases

Kim, Young-Jo; Joo, Sun Hyung; Choi, Hyun-Jun; Kim, Ki‐Young

doi:10.1155/2017/5049532

Cited by 32 publications

(21 citation statements)

References 53 publications

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“…As mentioned in the introduction, GSTO1 has been shown to be involved in the reactive oxygen species pathway; this finding, while not novel, shows that GSTO1 coexpression in TCGA patient cohorts is able to recapitulate known canonical biological function of GSTO1. In addition, several reports indicate that GSTO1 plays important roles in neurodegenerative diseases (35,36) and inflammation (17,19). This validates our coexpression analysis, and highlights the novelty of our findings.…”

Section: Integrated Transcriptional Profiles Across Cell Lines Revealsupporting

confidence: 89%

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

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Tian

et al. 2020

Cancer Research

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◥ GST omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we have validated GSTO1 as an impactful target in oncology. Transcriptional profiling coupled with proteomics uncovered novel pharmacodynamic markers and cellular pathways regulated by GSTO1. CRISPR/Cas9 GSTO1 knockout (KO) cell lines failed to form tumors or displayed growth delay in vivo; they also formed smaller 3D spheroids in vitro. Multiomics analysis in GSTO1 KO cells found a strong positive correlation with cell adhesion molecules and IFN response pathways and a strong negative correlation with Myc transcriptional signature. In addition, several clinically used drugs showed significant synthetic lethality with loss or inhibition of GSTO1. Transcription and protein expression of tissue factor (gene name, F3) were downregulated in response to GSTO1 KO. F3 is associated with poor patient survival and promotion of tumor progression in multiple cancers and is a known risk factor for metastasis. Transcription of F3 was regulated by IL1b, whose secretion decreased upon inhibition of GSTO1, suggesting that IL1b links GSTO1 expression and F3 transcription. In summary, our results implicate GSTO1 as a potential therapeutic target in cancer and offer new mechanistic insights into its significant role in cancer progression. Significance: These findings validate GSTO1 as a therapeutic target in cancer and implicate GSTO1 in the modulation of tumor growth, immune responses, and expression of F3.

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Section: Integrated Transcriptional Profiles Across Cell Lines Revealsupporting

confidence: 89%

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

Bankhead

Tian

et al. 2020

Cancer Research

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“…GSTO1 overexpression in transgenic Caenorhabditis elegans was observed to impart resistance to oxidative stress generated by numerous pro‐oxidants . GSTO1 was also observed to play a major role in neuroprotection against hydrogen peroxide‐induced neurotoxicity by regulating the mitogen‐activated protein kinase signaling pathway . In addition, GSTO1 has been reported to scavenge free radicals generated by inorganic arsenic, monomethylarsonate and dimethylarsonate via regulation of Docosahexaenoic acid (DHA) reduction .…”

Section: Discussionmentioning

confidence: 99%

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

et al. 2019

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Glutathione S‐transferase omega 1 (GSTO1) contributes to the inactivation of a wide range of drug compounds via conjugation to glutathione during phase reactions. Chemotherapy‐induced GSTO1 expression in breast cancer cells leads to chemoresistance and promotes metastasis. In search of novel GSTO1 inhibitors, we identified S2E, a thia‐Michael adduct of sulfonamide chalcone with low LC50 (3.75 ± 0.73 μm) that binds to the active site of GSTO1, as revealed by molecular docking (glide score: −8.1), cellular thermal shift assay and fluorescence quenching assay (Kb ≈ 10 × 105 mol·L−1). Docking studies confirmed molecular interactions between GSTO1 and S2E, and identified the hydrogen bond donor Val‐72 (2.14 Å) and hydrogen bond acceptor Ser‐86 (2.77 Å). Best pharmacophore hypotheses could effectively map S2E and identified the 4‐methyl group of the benzene sulfonamide ring as crucial to its anti‐cancer activity. Lack of a thiophenyl group in another analog, 2e, reduced its efficacy as observed by cytotoxicity and pharmacophore matching. Furthermore, GSTO1 inhibition by S2E, along with tamoxifen, led to a significant increase in apoptosis and decreased migration of aggressive MDA‐MB‐231 cells, as well as significantly decreased migration, invasion and mammosphere formation in sorted breast cancer stem cells (CSCs, CD24−/CD44+). GSTO1 silencing in breast CSCs also significantly increased apoptosis and decreased migration. Mechanistically, GSTO1 inhibition activated the c‐Jun N‐terminal kinase stress kinase, inducing a mitochondrial apoptosis signaling pathway in breast CSCs via the pro‐apoptotic proteins BAX, cytochrome c and cleaved caspase 3. Our study elucidated the role of the GSTO1 inhibitor S2E as a potential therapeutic strategy for preventing chemotherapy‐induced breast CSC‐mediated cancer metastasis and recurrence.

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“…GSTs play an important role in cellular oxidative damage, carcinogens, and drugs. Among the GST classes, several studies have found that the omega class GST (GSTO) is responsible for the detoxification of exogenous stress [11]. Under oxidative stress conditions, GSTO-1 overexpression in Caenorhabditis elegans has been found to increase the resistance to oxidative damage [12].…”

Section: Introductionmentioning

confidence: 99%

Glutathione S-Transferase Rescues Motor Neuronal Toxicity in Fly Model of Amyotrophic Lateral Sclerosis

et al. 2020

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Transactive response DNA-binding protein-43 (TDP-43) is involved in the pathology of familial and sporadic amyotrophic lateral sclerosis (ALS). TDP-43-mediated ALS models in mice, Drosophila melanogaster, and zebrafish exhibit dysfunction of locomotor function, defective neuromuscular junctions, and motor neuron defects. There is currently no effective cure for ALS, and the underlying mechanisms of TDP-43 in ALS remain poorly understood. In this study, a genetic screen was performed to identify modifiers of human TDP-43 (hTDP-43) in a Drosophila model, and glutathione S-transferase omega 2 (GstO2) was found to be involved in hTDP-43 neurotoxicity. GstO2 overexpressed on recovered defective phenotypes resulting from hTDP-43, including defective neuromuscular junction (NMJ) boutons, degenerated motor neuronal axons, and reduced larvae and adult fly locomotive activity, without modulating the levels of hTDP-43 protein expression. GstO2 modulated neurotoxicity by regulating reactive oxygen species (ROS) produced by hTDP-43 in the Drosophila model of ALS. Our results demonstrated that GstO2 was a key regulator in hTDP-43-related ALS pathogenesis and indicated its potential as a therapeutic target for ALS.

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Omega Class Glutathione S‐Transferase: Antioxidant Enzyme in Pathogenesis of Neurodegenerative Diseases

Cited by 32 publications

References 53 publications

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

Glutathione S-Transferase Rescues Motor Neuronal Toxicity in Fly Model of Amyotrophic Lateral Sclerosis

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