Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells

Biswas, Ayan; Khanna, Savita; Spieldenner, James M.; Pan, Xueliang; Sen, Chandan K.

doi:10.1074/jbc.m115.688879

Cited by 25 publications

(28 citation statements)

References 81 publications

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“…Under conditions of oxidant attack, GSH is rapidly converted to GSSG, making the elevation of the intracellular GSSG/GSH ratio a widely accepted marker for oxidative stress. GSSG generated in these processes can be either recycled to GSH by a NADPH-dependent reaction, catalyzed by GR 3 , or pumped out of the cell by ATP-dependent processes, with multidrug resistance-associated protein-1 (MRP-1) being the major pathway for GSSG efflux 33 . Although GSSG represents approximately 1% of the total glutathione in the cell under basal conditions, a striking increase is found in cells undergoing oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, in mouse embryonic stem cells, targeted disruption of glucose-6-phosphate dehydrogenase, which is the rate-limiting enzyme in the pentose phosphate pathway, the predominant metabolic pathway for the generation of NADPH (a cofactor of GR), renders cells extremely sensitive to H 2 O 2 -induced cell death 34 . Moreover, MRP-1 gene silencing results in cellular GSSG accumulation and cell death 33 . Studies with exogenous GSSG supplementation have documented that GSSG exposure is associated with apoptosis induction involving the p38 mitogen-activated protein kinase pathway 35 .…”

Section: Discussionmentioning

confidence: 99%

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Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease

Dou

et al. 2018

Exp Mol Med

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Oxidative stress and TNFα are critically involved in the initiation and progression of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of dysregulated glutathione homeostasis, a principal feature of oxidative stress, on TNFα-induced hepatotoxicity and its mechanistic implications in NAFLD progression. We showed that mice fed a high-fat diet (HFD) for 12 weeks developed hepatic steatosis and liver injuries, which were associated with not only TNFα overproduction but also hepatic glutathione dysregulation, characterized by GSH reduction and GSSG elevation. Moreover, consuming a HFD increased protein S-glutathionylation (protein-SSG formation) in the liver. Subsequent cell culture studies revealed that GSSG accumulation, as opposed to GSH reduction, sensitized hepatocytes to TNFα killing by reducing the TNFα-triggered NF-κB activity. GSSG prevented TNFα-induced activation of IKK-β, an upstream kinase in the NF-κB signaling pathway, by inducing IKK-β glutathionylation (IKK-β-SSG formation). In animal studies, in comparison to a control diet, HFD consumption resulted in increased hepatic IKK-β-SSG formation, leading to suppressed IKK-β activation and subsequent NF-κB suppression. Furthermore, we found that HFD consumption also led to decreased hepatic expression of glutaredoxin, a key enzyme for de-glutathionylation. Similarly, CdCl2, a chemical inhibitor of glutaredoxin, sensitized hepatocytes to TNFα-mediated cytotoxicity. In conclusion, our data suggest that GSSG is a potent and clinically relevant sensitizer for TNFα-induced hepatotoxicity in NAFLD, which represents a potential therapeutic target for NAFLD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease

Dou

et al. 2018

Exp Mol Med

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“…Results of qPCR were reported as fold change in the target gene relative to the endogenous control miR and calculated using the 2 −Δ(ΔCt) method as previously described (18, 20–22):…”

Section: Methodsmentioning

confidence: 99%

Urinary Excretion of MicroRNA-126 Is a Biomarker for Hemangioma Proliferation

Biswas

Pan

Meyer

et al. 2017

Plastic &Amp; Reconstructive Surgery

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Background Hemangiomas are unique endothelial cell tumors that spontaneously involute, which makes it difficult to interpret response to therapies. The objective of this work was to identify a potential biomarker in the urine of children with infantile hemangiomas that would facilitate testing new therapies. Methods A prospective longitudinal study in children with hemangiomas and age matched healthy controls was performed to determine whether microRNA (miR)-126, which is highly abundant in fetal endothelial cells, was more abundant in the urine of affected children. Prospective ultrasound measurements of hemangioma size and blood flow velocity were obtained as secondary endpoints to document longitudinal changes in untreated hemangiomas. Results Urinary miR-126 levels were significantly elevated in children with proliferating hemangiomas and relative levels of urinary miR abundance correlated with hemangioma size. Hemangiomas had elevated levels of miR abundance compared to healthy controls. Ultrasound data revealed that hemangioma proliferation typically stopped between 6 to 9 months of age. When hemangioma proliferation stopped urinary miR-126 levels in children with hemangiomas dropped to levels observed in healthy age matched controls. Conclusions These are the first reported results to identify a potential miR biomarker in the urine of children with hemangiomas. Measurement of urinary levels of miR-126 could potentially be used to monitor hemangioma response to therapies.

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“…[88,89] Despite most of the downstream genes synthesized upon activation of nF-kB, it was also reported with the capability of enhancing cancer cells invasion and metastasis and promote vascularization and angiogenesis in different manner thus give rise to high mortality rate of breast cancer patients. [90] Nevertheless, the cancer cells invasion assay used Previous studies of PTZ on A2780 ovarian cancer cells reported PTZ blocked the invasion of A2780 cells via inhibition of NF-kB gene BIRC6-XIAP complexes. [19] Based on the data summarised in Table 1 sistant to apoptotic cell death.…”

Section: Genesmentioning

confidence: 99%

10H‐3,6‐Diazaphenothiazines triggered the mitochondrial‐dependent and cell death receptor‐dependent apoptosis pathways and further increased the chemosensitivity of MCF‐7 breast cancer cells via inhibition of AKT1 pathways

Ren

Hao

Yang

et al. 2020

J Biochem & Molecular Tox

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Breast cancer is one of the leading causes of death in cancer categories, followed by lung, colorectal, and ovarian among the female gender across the world. 10H‐3,6‐diazaphenothiazine (PTZ) is a thiazine derivative compound that exhibits many pharmacological activities. Herein, we proceed to investigate the pharmacological activities of PTZ toward breast cancer MCF‐7 cells as a representative in vitro breast cancer cell model. The PTZ exhibited a proliferation inhibition (IC50 = 0.895 µM) toward MCF‐7 cells. Further, cell cycle analysis illustrated that the S‐phase checkpoint was activated to achieve proliferation inhibition. In vitro cytotoxicity test on three normal cell lines (HEK293 normal kidney cells, MCF‐10A normal breast cells, and H9C2 normal heart cells) demonstrated that PTZ was more potent toward cancer cells. Increase in the levels of reactive oxygen species results in polarization of mitochondrial membrane potential (ΔΨm), together with suppression of mitochondrial thioredoxin reductase enzymatic activity suggested that PTZ induced oxidative damages toward mitochondria and contributed to improved drug efficacy toward treatment. The RT2 PCR Profiler Array (human apoptosis pathways) proved that PTZ induced cell death via mitochondria‐dependent and cell death receptor‐dependent pathways, through a series of modulation of caspases, and the respective morphology of apoptosis was observed. Mechanistic studies of apoptosis suggested that PTZ inhibited AKT1 pathways resulting in enhanced drug efficacy despite it preventing invasion of cancer cells. These results showed the effectiveness of PTZ in initiation of apoptosis, programmed cell death, toward highly chemoresistant MCF‐7 cells, thus suggesting its potential as a chemotherapeutic drug.

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Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells

Cited by 25 publications

References 81 publications

Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease

Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease

Urinary Excretion of MicroRNA-126 Is a Biomarker for Hemangioma Proliferation

10H‐3,6‐Diazaphenothiazines triggered the mitochondrial‐dependent and cell death receptor‐dependent apoptosis pathways and further increased the chemosensitivity of MCF‐7 breast cancer cells via inhibition of AKT1 pathways

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