2-Deoxyglucose Induces Noxa-Dependent Apoptosis in Alveolar Rhabdomyosarcoma

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 abilitytoactivateBaxandBak.OverexpressionoftheantiapoptoticBcl-2homologuesBcl-xLandMcl-1prevented 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 eIF2a 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 andthatNoxacouldoffer aprognostic markertomonitortheefficacyofsuchagents.Cancer Res;71(21); 6796–806. � 2011 AACR.