Abstract
Targeting altered cancer cell metabolism with the glycolysis inhibitor, 2-deoxyglucose (2DG), is a viable therapeutic strategy, but the effects of 2DG on lymphoma cells and the mechanism of action are unknown. Five T-cell lymphoma lines and two B-cell lymphoma lines were shown to be highly sensitive to 2DG. Examination of the cell death pathway demonstrated pro-apoptotic protein Bax 'activation' and caspase cleavage in 2DG-treated cells. However, Q-VD-OPh, a potent inhibitor of caspase activity provided minimal protection from death. In contrast, overexpressing the anti-apoptotic protein Bcl-2 dramatically enhanced the survival of 2DG-treated cells that was negated by a Bcl-2 antagonist. BH3-only members, Bim and Bmf, were upregulated by 2DG, and shRNAs targeting Bim protected from 2DG toxicity demonstrating that Bim is a critical mediator of 2DG toxicity. 2DG also induced GADD153/CHOP expression, a marker of endoplasmic reticulum (ER) stress and a known activator of Bim. Mannose, a reagent known to alleviate ER stress, transiently protected from 2DG-induced cell death. Examination of the effects of 2DG on energy metabolism showed a drop in ATP levels by 30 min that was not affected by either Bcl-2 or mannose. These results demonstrate that ER stress appears to be rate limiting in 2DG-induced cell death in lymphoma cells, and this cell killing is regulated by the Bcl-2 family of proteins. Bcl-2 inhibition combined with 2DG may be an effective therapeutic strategy for lymphoma.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antimetabolites / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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Bcl-2-Like Protein 11
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Biphenyl Compounds / pharmacology
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Blotting, Western
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Caspases / metabolism
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Cell Proliferation
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Cells, Cultured
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Deoxyglucose / pharmacology*
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Flow Cytometry
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Immunoprecipitation
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Lymphoma, B-Cell / drug therapy*
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Lymphoma, B-Cell / metabolism
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Lymphoma, B-Cell / pathology
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Lymphoma, T-Cell / drug therapy*
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Lymphoma, T-Cell / metabolism
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Lymphoma, T-Cell / pathology
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Nitrophenols / pharmacology
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Piperazines / pharmacology
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfonamides / pharmacology
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Thymocytes / cytology
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Thymocytes / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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ABT-737
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Antimetabolites
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Biphenyl Compounds
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Membrane Proteins
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Sulfonamides
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bcl-2-Associated X Protein
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Deoxyglucose
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Caspases