title: 2-deoxyglucose induces Noxa-dependent apoptosis in alveolar rhabdomyosarcoma.
abstract: Alveolar and embryonal rhabdomyosarcomas are childhood tumors that do not respond well to current chemotherapies. Here, we report that the glycolytic inhibitor 2-deoxyglucose (2-DG) can efficiently promote cell death in alveolar, but not embryonal, rhabdomyosarcoma cell lines. Notably, 2-DG also induced cell differentiation accompanied by downregulation of PAX3/FOXO1a, the chromosome translocation-encoded fusion protein that is a central oncogenic driver in this disease. Cell death triggered by 2-DG was associated with its ability to activate Bax and Bak. Overexpression of the antiapoptotic Bcl-2 homologues Bcl-x(L) and Mcl-1 prevented apoptosis, indicating that cell death proceeds through the mitochondrial pathway. Mechanistic investigations indicated that Mcl-1 downregulation and Noxa upregulation were critical for 2-DG-induced apoptosis. In addition, 2-DG promoted eIF2α phosphorylation and inactivation of the mTOR pathway. Mcl-1 loss and cell death were prevented by downregulation of the endoplasmic reticulum (ER) stress-induced protein ATF4 and by incubating cells in the presence of mannose, which reverted 2-DG-induced ER stress but not ATP depletion. Thus, energetic stresses created by 2-DG were not the primary cause of cell death. Together, our findings suggest that glycolysis inhibitors such as 2-DG may be highly effective in treating alveolar rhabdomyosarcoma and that Noxa could offer a prognostic marker to monitor the efficacy of such agents.
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ramírez-Peinado
authors.forename: Fermín
authors.initials: F
authors.lastname: Alcázar-Limones
authors.forename: Laura
authors.initials: L
authors.lastname: Lagares-Tena
authors.forename: Nadia
authors.initials: N
authors.lastname: El Mjiyad
authors.forename: Alfredo
authors.initials: A
authors.lastname: Caro-Maldonado
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Tirado
authors.forename: Cristina
authors.initials: C
authors.lastname: Muñoz-Pinedo
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008358:Mannose / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018232:Rhabdomyosarcoma, Alveolar / Q000378:metabolism / Q000473:pathology*; D018233:Rhabdomyosarcoma, Embryonal / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D015852:Eukaryotic Initiation Factor-2; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D003847:Deoxyglucose; D008358:Mannose