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Research ArticleArticle

Glutathione Peroxidase-1 Overexpression Prevents Ceramide Production and Partially Inhibits Apoptosis in Doxorubicin-Treated Human Breast Carcinoma Cells

Valérie Gouazé, Marc-Edouard Mirault, Stéphane Carpentier, Robert Salvayre, Thierry Levade and Nathalie Andrieu-Abadie
Molecular Pharmacology September 2001, 60 (3) 488-496;
Valérie Gouazé
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Marc-Edouard Mirault
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Stéphane Carpentier
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Robert Salvayre
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Thierry Levade
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Nathalie Andrieu-Abadie
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Abstract

Reduced glutathione and N-acetylcysteine can inhibit both apoptosis and necrosis of several cell types, suggesting a critical role for reactive oxygen species (ROS) in cell death. However, how the cellular defense against oxidative stress is connected with other cell death mediators remains unclear. We selectively investigated the interaction of seleno-glutathione peroxidase-1 (GPx-1), the major enzyme responsible for peroxide detoxification in mammalian cells, with the cytotoxic response of T47D human breast cancer cells to doxorubicin, an anticancer drug known to promote production of ROS and apoptotic mediator ceramide. The sensitivity to doxorubicin-mediated cell death was compared in T47D/H3 containing low levels of endogenous GPx and T47D/GPx2 transfectant cells, which overexpress GPx-1. We show that T47D/GPx2 cells were significantly more resistant than T47D/H3 cells to doxorubicin (1 μM). The glutathione precursor,N-acetylcysteine also partially protected T47D/H3 cells from the lethal effect of doxorubicin, whereasl-buthionine-(S,R)-sulfoximine, an inhibitor of glutathione biosynthesis, sensitized both GPx-1–deficient and -proficient cells. Interestingly, in addition to a decrease in ROS production, the activation of neutral sphingomyelinase, sphingomyelin hydrolysis, and ceramide generation in response to doxorubicin was impaired in T47D/GPx2 cells compared with control cells. In contrast, GPx overexpression did not protect breast cancer cells from cell death induced by exogenous cell-permeant ceramide. Moreover, the basal activity of neutral sphingomyelinase was considerably lower in T47D/GPx2. Taken together, these results indicate that GPx-1 can regulate doxorubicin-induced cell death signaling at least in part by interfering with the activation of the sphingomyelin-ceramide pathway.

Footnotes

  • This work was supported by grants from INSERM, UniversitéP. Sabatier, and from the NCI of Canada (to M.-E.M.). V.G. is a recipient of the Association pour la Recherche contre le Cancer and the Ligue Régionale Contre le Cancer fellowships.

  • Abbreviations:
    ROS
    reactive oxygen species
    GSH
    glutathione
    BSO
    l-buthionine-(S,R)-sulfoximine
    TNF
    tumor necrosis factor
    GPx
    glutathione peroxidase
    SMase
    sphingomyelinase
    SM
    sphingomyelin
    NAC
    N-acetylcysteine
    DAPI
    4′,6-diamidino-2-phenylindole
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    DCFH-DA
    6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate, di(acetoxymethyl ester
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
    • Received April 30, 2001.
    • Accepted June 11, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Glutathione Peroxidase-1 Overexpression Prevents Ceramide Production and Partially Inhibits Apoptosis in Doxorubicin-Treated Human Breast Carcinoma Cells

Valérie Gouazé, Marc-Edouard Mirault, Stéphane Carpentier, Robert Salvayre, Thierry Levade and Nathalie Andrieu-Abadie
Molecular Pharmacology September 1, 2001, 60 (3) 488-496;

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Research ArticleArticle

Glutathione Peroxidase-1 Overexpression Prevents Ceramide Production and Partially Inhibits Apoptosis in Doxorubicin-Treated Human Breast Carcinoma Cells

Valérie Gouazé, Marc-Edouard Mirault, Stéphane Carpentier, Robert Salvayre, Thierry Levade and Nathalie Andrieu-Abadie
Molecular Pharmacology September 1, 2001, 60 (3) 488-496;
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