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2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production

DJAVAHERI-MERGNY, Mojgan ; WIETZERBIN, Juana ; BESANCON, Francoise

Oncogene, 2003-05, Vol.22 (17), p.2558-2567 [Periódico revisado por pares]

Basingstoke: Nature Publishing

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Título:
2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production
Autor: DJAVAHERI-MERGNY, Mojgan ; WIETZERBIN, Juana ; BESANCON, Francoise
Assuntos: 17β-Estradiol ; Antineoplastic Agents - pharmacology ; Antioxidants - metabolism ; Apoptosis ; Apoptosis - drug effects ; Biological and medical sciences ; Bone tumors ; c-Jun protein ; Caspase-9 ; Caspases - drug effects ; Cell activation ; Cell death ; Cell Division - drug effects ; Chemical mutagenesis ; Chromosomes ; Cytochrome ; Cytochrome c ; Electron transport ; Estradiol - analogs & derivatives ; Estradiol - pharmacology ; Estrogens ; Ewing's sarcoma ; Ewings sarcoma ; Humans ; Hydrogen Peroxide ; JNK protein ; Kinases ; Lipid peroxidation ; Medical sciences ; Membrane potential ; Metastases ; Metastasis ; Mitochondria ; Mitogen-Activated Protein Kinases - drug effects ; p53 Protein ; Reactive oxygen species ; Receptors, Tumor Necrosis Factor - drug effects ; Rotenone ; Sarcoma, Ewing - drug therapy ; Toxicology ; Transcription factors ; Tumor Cells, Cultured ; Tumors ; Vitamin E ; Young adults
É parte de: Oncogene, 2003-05, Vol.22 (17), p.2558-2567
Notas: ObjectType-Article-2
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Descrição: The Ewing sarcoma is the second most common bone tumor in children and young adults. Despite the advances in therapy, the 5-year survival rate for patients with metastatic disease is poor, indicating the need for alternative treatments. Here, we report that 2-methoxy-estradiol (2-Me), a natural estrogen metabolite, induced a caspase-dependent apoptosis of Ewing sarcoma-derived cells independently of their p53 status. 2-Me-induced apoptosis occurred through the mitochondrial death pathway as evidenced by reduction of the mitochondrial transmembrane potential, cytochrome c release and caspase-9 activation. Treatment of cells with 2-Me resulted in generation of intracellular H(2)O(2), which occurred earlier than caspase-9 activation. The H(2)O(2)-reducing agent Ebselen and the lipid peroxidation inhibitor vitamin E decreased both 2-Me-induced caspase-9 activation and cell death, thus providing evidence for a role of H(2)O(2) and lipid peroxides in the initiation of this process. Rotenone, an inhibitor of the mitochondrial respiratory chain, abolished both apoptosis and H(2)O(2) production, thereby identifying mitochondria as the source of H(2)O(2). Moreover, we observed that treatment of cells with 2-Me or H(2)O(2) induced activation of the c-Jun N-terminal kinase (JNK). Overexpression of a dominant-negative mutant of JNK1 reduced 2-Me-induced apoptosis indicating that JNK participates in this process. Altogether, our results provide evidence that 2-Me triggers apoptosis of Ewing sarcoma cells through induction of a mitochondria redox-dependent mechanism and suggest that this compound or other agents that selectively increase the level of reactive oxygen species may prove useful to the development of novel strategies for treatment of Ewing tumors.
Editor: Basingstoke: Nature Publishing
Idioma: Inglês

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2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production

DJAVAHERI-MERGNY, Mojgan ; WIETZERBIN, Juana ; BESANCON, Francoise

Basingstoke: Nature Publishing

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