c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagyand apoptosis in 2-methoxyestradiol-treated ewing sarcoma cells

Séverine Lorin, Amélie Borges, Lisandra Ribeiro Dos Santos, Sylvie Souquère, Gérard Pierron, Kevin M. Ryan, Patrice Codogno, Mojgan Djavaheri-Mergny

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

70 Citations (Scopus)

Résumé

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.

langue originaleAnglais
Pages (de - à)6924-6931
Nombre de pages8
journalCancer Research
Volume69
Numéro de publication17
Les DOIs
étatPublié - 1 sept. 2009
Modification externeOui

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