title: c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagy and apoptosis in 2-methoxyestradiol-treated Ewing sarcoma cells.
abstract: 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 NH(2)-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U756, Faculté de Pharmacie, Université Paris-Sud 11, Châtenay-Malabry, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Lorin
authors.forename: Amélie
authors.initials: A
authors.lastname: Borges
authors.forename: Lisandra
authors.initials: L
authors.lastname: Ribeiro Dos Santos
authors.forename: Sylvie
authors.initials: S
authors.lastname: Souquère
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Ryan
authors.forename: Patrice
authors.initials: P
authors.lastname: Codogno
authors.forename: Mojgan
authors.initials: M
authors.lastname: Djavaheri-Mergny
mesh_terms: D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008565:Membrane Proteins; D011506:Proteins / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C512709:DRAM1 protein, human; D008565:Membrane Proteins; D011506:Proteins; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D000077584:2-Methoxyestradiol; D048031:JNK Mitogen-Activated Protein Kinases