Glutathione depletion up‐regulates Bcl‐2 in BSO‐resistant cells

D'alessio, Maria; Cerella, Claudia; Amici, Carla; Pesce, Caterina Delfina; Coppola, Simona; Fanelli, C.; Nicola, Milena De; Cristofanon, Silvia; Clavarino, Giovanna; Bergamaschi, Antonio; Magrini, Andrea; Gualandi, G; Ghibelli, Lina

doi:10.1096/fj.04-1813fje

Cited by 49 publications

(58 citation statements)

References 37 publications

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“…In cholangiocytes, GSH depletion down-regulated Bcl-2 by reducing its half-life (Celli et al, 1998), whereas in human colon cancer cells, NAC-induced elevation in GSH level was accompanied with increased Bcl-2 expression (Ho et al, 1997). D'Alessio et al (2004) isolated two tumor cell lines (from U937 and HEpG2 cells) resistant to BSO treatment that up-regulate Bcl-2 in response to BSO. We did not observe difference in Bcl-2 expression after GSH depletion or after increase in GSH levels by NAC treatment in human laryngeal carcinoma cells (data not shown), suggesting no interaction between Bcl-2 and GSH in HEp2 cells and presence of at least two signaling pathways triggered by ␣ v ␤ 3 integrin.…”

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confidence: 99%

“…Bcl-2 overexpression causes redistribution of GSH to the nucleus, thereby altering nuclear redox potential (Voehringer et al, 1998) and by raising cellular antioxidant defense status decreases formation of some oxidative reactive nitrogen species (Lee et al, 2001). However, U937 monocytic tumor cells treated with buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, up-regulated Bcl-2 expression that supported their survival (D'Alessio et al, 2004). In contrast, BSO caused GSH depletion down-regulated Bcl-2 by reducing protein half-life and induced cholangiocyte apoptosis (Celli et al, 1998).…”

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confidence: 99%

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α_vβ₃ Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Brozović

Majhen²,

Roje³

et al. 2008

Mol Pharmacol

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As a model for determination of the role of integrins in drug resistance, we used ␣ v ␤ 3 integrin-negative human laryngeal carcinoma cell line (HEp2) and three HEp2-derived cell clones with a gradual increase of ␣ v ␤ 3 integrin expression. The ␣ v ␤ 3 integrin expression protects cells from cisplatin, mitomycin C, and doxorubicin. In HEp2-␣ v ␤ 3 integrin-expressing cells, the constitutive expression of Bcl-2 protein and the level of glutathione (GSH) were increased compared with HEp2 cells. Pretreatment of HEp2-␣ v ␤ 3 integrin-expressing cells with an inhibitor of GSH synthesis, buthionine sulfoximine (BSO), decreased the level of GSH and partially reverted drug resistance to all above-mentioned drugs, but it did not influence the expression of Bcl-2. Sensitivity to selected anticancer drugs did not change with overexpression of Bcl-2 in HEp2 cells, nor with silencing of Bcl-2 in HEp2-␣ v ␤ 3 integrin-expressing cells, indicating that Bcl-2 is not involved in resistance mechanism. There was no difference in DNA platination between HEp2 and HEp2-␣ v ␤ 3 integrin-expressing cells, indicating that the mechanism of drug resistance is independent of cisplatin detoxification by GSH. A strong increase of reactive oxidative species (ROS) formation during cisplatin or doxorubicin treatment in HEp2 cells was reduced in HEp2-␣ v ␤ 3 integrin-expressing cells. Since this increased elimination of ROS could be reverted by GSH depletion, we concluded that multidrug resistance is the consequence of GSH-dependent increased ability of ␣ v ␤ 3 -expressing cells to eliminate drug-induced ROS.Chemotherapy often results in the development of drug resistance. Several molecular mechanisms have been recognized as a cause of resistance, such as reduced drug accumulation, increased drug inactivation, increased ability to repair and/or tolerate DNA lesions, and inhibition of apoptosis. Recent findings show that integrin-mediated adhesion to the extracellular matrix can modify cellular response to chemotherapeutic drugs through mechanisms such as inhibition of apoptosis, decreased cellular proliferation, and alterations in a drug target (Damiano, 2002;Ambriović-Ristov and Osmak, 2006). Integrins are cell surface adhesion molecules that connect cells to components of the extracellular matrix. They are assembled from a set of diverse ␣-(18) and ␤-(8) subunits that associate to form 24 differentially composed heterodimers exhibiting specific but also redundant ligand binding and expression patterns. Integrins modulate many signaling pathways, supporting cell survival and proliferation and influencing expression of differentiation-regulated genes (Danen, 2005).The most extensively used model for investigation of molecular mechanisms of drug resistance is the development of resistant cells by selected anticancer drug treatment and then comparing the biological and biochemical characteristics of those cells, allowing for the causes of drug resistance to be determined. Despite increased expression of several integrin subunits and/or he...

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confidence: 99%

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confidence: 99%

α_vβ₃ Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Brozović

Majhen²,

Roje³

et al. 2008

Mol Pharmacol

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“…CySS is the predominant form in the plasma, and extensive research has characterized Cys and CySS transport systems (2) and utilization of Cys and CySS for cell growth (3,27) and protection against oxidative stress (4). Inhibition of Cys incorporation into GSH by L-buthionine-[S,R]-sulfoximine (BSO) sensitizes many cell types to anticancer therapy (6), and supply of N-acetyl-L-cysteine and other Cys precursors is a common approach to enhance antioxidant defenses (21).…”

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confidence: 99%

Control of extracellular cysteine/cystine redox state by HT-29 cells is independent of cellular glutathione

Anderson

Iyer

Ziegler

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Human cell lines regulate the redox state (Eh) of the cysteine/cystine (Cys/CySS) couple in culture medium to approximately −80 mV, a value similar to the average Eh for Cys/CySS in human plasma. The mechanisms involved in regulation of extracellular Eh of Cys/CySS are not known, but GSH is released from tissues at rates proportional to tissue GSH concentration, and this released GSH could react with CySS to contribute to maintenance of this balance. The present study was undertaken to determine whether depletion of cellular GSH alters regulation of extracellular Cys/CySS Eh. Decrease of GSH in HT-29 cells by inhibiting synthesis with l-buthionine-[ S, R]-sulfoximine showed no effect on the rate of reduction of extracellular CySS to achieve a stable Eh for Cys/CySS in the culture medium. Limiting Cys and CySS in the culture medium also substantially decreased cellular GSH but resulted in no significant effect on extracellular Cys/CySS Eh. Addition of CySS to these cells showed that extracellular Cys/CySS Eh approached −80 mV at 4 h while cellular GSH and extracellular GSH/GSSG Eh recovered more slowly. Together, these results show that HT-29 cells have the capacity to regulate the extracellular Cys/CySS Eh by mechanisms that are independent of cellular GSH. The results suggest that transport systems for Cys and CySS and/or membranal oxidoreductases could be more important than cellular GSH in regulation of extracellular Cys/CySS Eh.

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“…The antioxidant glutathione is part of one of the most important redox system in mammalian cells. 44 Buthionine sulfoximine (BSO) is known to deplete glutathione, 45,46 which in turn increases ROS levels. Consistently, when mice were treated with BSO, elevated ROS production could be observed in granulocytes (Figures 6a).…”

Section: Glutathione Depletion By Buthionine Sulfoximine Influences Cd8mentioning

confidence: 99%

Reactive oxygen species delay control of lymphocytic choriomeningitis virus

Xu¹,

Mcllwain²,

Pandyra³

et al. 2014

Z Gastroenterol

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Cluster of differentiation (CD)8þ T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8þ T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1 À / À ) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.

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Glutathione depletion up‐regulates Bcl‐2 in BSO‐resistant cells

Cited by 49 publications

References 37 publications

α_vβ₃ Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

α_vβ₃ Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Control of extracellular cysteine/cystine redox state by HT-29 cells is independent of cellular glutathione

Reactive oxygen species delay control of lymphocytic choriomeningitis virus

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Glutathione depletion up‐regulates Bcl‐2 in BSO‐resistant cells

Cited by 49 publications

References 37 publications

αvβ3 Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

αvβ3 Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Control of extracellular cysteine/cystine redox state by HT-29 cells is independent of cellular glutathione

Reactive oxygen species delay control of lymphocytic choriomeningitis virus

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α_vβ₃ Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

α_vβ₃ Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species