c-Jun NH2-Terminal Kinase Activation Is Essential for DRAM-Dependent Induction of Autophagy and Apoptosis in 2-Methoxyestradiol–Treated Ewing Sarcoma Cells
In: Cancer Research, Jg. 69 (2009-08-31), S. 6924-6931
Online
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Zugriff:
Ewing sarcoma and osteosarcoma are two aggressive cancers that affect bones and soft tissues in children and adolescents. Despite multimodal therapy, patients with metastatic sarcoma have a poor prognosis, emphasizing a need for more effective treatment. We have shown previously that 2-methoxyestradiol (2-ME), an antitumoral compound, induces apoptosis in Ewing sarcoma cells through c-Jun NH2-terminal kinase (JNK) activation. In the present study, we provide evidence that 2-ME elicits macroautophagy, a process that participates in apoptotic responses, in a JNK-dependent manner, in Ewing sarcoma and osteosarcoma cells. We also found that the enhanced activation of JNK by 2-ME is partially regulated by p53, highlighting the relationship of JNK and autophagy to p53 signaling pathway. Furthermore, we showed that 2-ME up-regulates damage-regulated autophagy modulator (DRAM), a p53 target gene, in Ewing sarcoma cells through a mechanism that involves JNK activation. The silencing of DRAM expression reduced both apoptosis and autophagy triggered by 2-ME in Ewing sarcoma and osteosarcoma cells. Our results therefore identify JNK as a novel mediator of DRAM regulation. These findings suggest that 2-ME or other anticancer therapies that increase DRAM expression or function could be used to effectively treat sarcoma patients. [Cancer Res 2009;69(17):6924–31]
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c-Jun NH2-Terminal Kinase Activation Is Essential for DRAM-Dependent Induction of Autophagy and Apoptosis in 2-Methoxyestradiol–Treated Ewing Sarcoma Cells
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Autor/in / Beteiligte Person: | Ryan, Kevin M. ; Borges, Amélie ; Pierron, Gérard ; Souquere, Sylvie ; Codogno, Patrice ; Djavaheri-Mergny, Mojgan ; Lorin, Séverine ; Lisandra Ribeiro Dos Santos ; Signalisation et physiopathologie des cellules épithéliales ; Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Génétique moléculaire et intégration des fonctions cellulaires (GMIFC) ; Centre National de la Recherche Scientifique (CNRS) ; Institut André Lwoff - Biologie intégrée de la cellule, virus et cancer (IALBICVC) ; Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; The Beatson Institute for Cancer Research ; University of Glasgow |
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Zeitschrift: | Cancer Research, Jg. 69 (2009-08-31), S. 6924-6931 |
Veröffentlichung: | American Association for Cancer Research (AACR), 2009 |
Medientyp: | unknown |
ISSN: | 1538-7445 (print) ; 0008-5472 (print) |
DOI: | 10.1158/0008-5472.can-09-1270 |
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