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.
Highlights
Rhabdomyosarcoma is the most common soft tissue tumor in children and adolescence, accounting for 4% to 5% of pediatric tumors
We analyzed the effects of 2-DG in a panel of alveolar rhabdomyosarcoma cell lines. 2-DG inhibited the growth of Rh4 alveolar rhabdomyosarcoma cells incubated with doses of 2 mmol/L or higher, even though glucose is present at 25 mmol/L in the culture medium (Supplementary Fig. S1)
We provide evidence here that an inhibitor of the glycolytic metabolism is effective against alveolar rhabdomyosarcoma
Summary
Rhabdomyosarcoma is the most common soft tissue tumor in children and adolescence, accounting for 4% to 5% of pediatric tumors. The 2 common histiotypes are a favorable group comprising embryonal rhabdomyosarcoma and an unfavorable group comprising alveolar rhabdomyosarcoma [1]. Standard therapeutic regimens are a combination of vincristine, actinomycin-D, and cyclophosphamide, with other drugs being tested in clinical trials [2]. Tumor metabolism is receiving an ever-increasing attention as an antitumor target. Several metabolic pathways function differently in tumor and nontransformed cells [4]. Glycolysis is frequently upregulated in tumor cells and respiration is inhibited.
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