Abstract 9: 2-deoxyglucose caused toxicity is regulated by the Bcl-2 family and is enhanced by Bcl-2 antagonist in lymphoma cell lines

Abstract

Abstract Introduction. 2-deoxyglucose (2DG) is a glucose analog and inhibitor of glycolysis that has been shown to have anti-cancer activity, proposed to be due to altered metabolism of cancer cells. 2DG has also been reported to induce ER stress through inhibition of N-linked glycosylation. Whether 2DG is effective in lymphoma and the mechanisms of cell death are not known. Materials and Methods. Five tumor cell lines were independently derived from Lck-Bax driven murine T cell lymphomas (TCLs). The sensitivity of these cell lines to 2DG was determined by plasma membrane integrity and clonogenic survival. Caspase inhibitors, overexpression of Bcl-2, downregulation of Bim, the Bcl-2 antagonist ABT-737, and mannose were utilized to determine the molecular mechanism of 2DG-caused death in lymphoma cell lines. Results and Conclusions. TCLs are uniformly sensitive to physiologically relevant concentrations of 2DG treatment. The cell death pathway involves Bax “activation” and Caspase cleavage following 2DG treatment. However, qVD-OPh effectively inhibited caspase activity while providing minimal protection from death. In contrast, expression of Bcl-2 enhanced both short term and clonogenic survival of 2DG treated cells. A Bcl-2 antagonist, ABT-737, sensitized TCLs to 2DG-induced cell death. Examination of BH3-only members demonstrated that both Bim and Bmf were upregulated following 2DG treatment. Importantly, downregulation of Bim with shRNAs protected from 2DG treatment, demonstrating that Bim is a critical mediator of 2DG toxicity. We also observed that 2DG led to CHOP induction, a transcription factor shown to directly mediate Bim upregulation following ER stress. Mannose, a reagent known to alleviate ER stress induced by 2DG, also transiently protected from cell death. While mannose effectively blocked CHOP upregulation, Bim upregulation was delayed but not blocked indicating that 2DG upregulated BIM and induced cell death by ER stress dependent and independent mechanism. However, both pathways converge at a step that involves the activation of Bax and is blocked by Bcl-2. We conclude that 2DG toxicity is regulated by the Bcl-2 family, and the combination of Bcl-2 inhibition and 2DG is a candidate for effective therapeutic strategy for lymphoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 9. doi:10.1158/1538-7445.AM2011-9