Journal article
2-Deoxyglucose-induced toxicity is regulated by Bcl-2 family members and is enhanced by antagonizing Bcl-2 in lymphoma cell lines
Oncogene, Vol.31(22), pp.2738-2749
05/31/2012
DOI: 10.1038/onc.2011.454
PMCID: PMC3257357
PMID: 21986940
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 (TCLs) and two B cell lymphoma lines (BCLs) were shown to be highly sensitive to 2DG. Examination of the cell death pathway demonstrated proapoptotic 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 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 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.
Details
- Title: Subtitle
- 2-Deoxyglucose-induced toxicity is regulated by Bcl-2 family members and is enhanced by antagonizing Bcl-2 in lymphoma cell lines
- Creators
- Oksana Zagorodna - Department of Pathology, University of Iowa, Iowa City, IASean M Martin - Department of Pathology, University of Iowa, Iowa City, IAD. Thomas Rutkowski - D Department of Anatomy & Cell Biology, University of Iowa, Iowa City, IATomomi Kuwana - Department of Pathology, University of Iowa, Iowa City, IADouglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center University of Iowa, Iowa City, IAC. Michael Knudson - Department of Pathology, University of Iowa, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.31(22), pp.2738-2749
- DOI
- 10.1038/onc.2011.454
- PMID
- 21986940
- PMCID
- PMC3257357
- NLM abbreviation
- Oncogene
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Language
- English
- Date published
- 05/31/2012
- Academic Unit
- Anatomy and Cell Biology; Pathology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047658002771
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