title: 2-deoxyglucose-induced toxicity is regulated by Bcl-2 family members and is enhanced by antagonizing Bcl-2 in lymphoma cell lines.
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.
authors: Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
authors: O
authors: O
authors: Zagorodna
authors: S M
authors: SM
authors: Martin
authors: D T
authors: DT
authors: Rutkowski
authors: T
authors: T
authors: Kuwana
authors: D R
authors: DR
authors: Spitz
authors: C M
authors: CM
authors: Knudson
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000494:pharmacology*; D005434:Flow Cytometry; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D000963:Antimetabolites; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D003847:Deoxyglucose; D020169:Caspases