Abstract 4840: 2-Deoxy-D-glucose induces autophagy through endoplasmic reticulum stress rather than by lowering ATP

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Abstract Based on emerging evidence that oncogenes direct increased glucose metabolism in tumor cells, the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) appears to be a promising drug to selectively target cancer cells. 2-DG however, not only blocks glycolysis and reduces cellular ATP production but also interferes with N-linked glycosylation, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Both bioenergetic challenge and ER stress/UPR have been shown to activate autophagy, a bulk cellular degradation process that plays either a pro- or anti-death role. This led us to investigate the following, 1) which pathway that 2-DG interferes with is responsible for stimulating autophagy, and 2) the role of autophagy in modulating 2-DG-induced cellular responses and toxicity. In four cancer cell lines (1420, MDA-MB-435, SKBR3 and T98G) we find that 2-DG upregulates autophagy (LC3B II), increases the ER stress/UPR markers, Grp78 and CHOP, and lowers ATP levels. Addition of exogenous mannose reverses 2-DG-induced autophagy and expression of GRP78 and CHOP but does not recover the lowered levels of ATP. Additionally, when autophagy is either blocked or enhanced by 3-methyladenine (3-MA) or rapamycin, respectively, 3-MA increases whereas rapamycin reduces cancer cell sensitivity to 2-DG. In support of these results, knock down of autophagy-related gene 7 (Atg7) with small interfering RNAs (siRNAs) increases sensitivity to 2-DG in 1420 cells, which correlates with increases in the ER stress/UPR markers as well as the apoptotic marker, cleaved caspase 3. Overall, these results indicate that the major mechanism by which 2-DG stimulates autophagy is through ER stress/UPR, and autophagy protects cells from 2-DG-induced toxicity through relief of ER stress. Thus, combining autophagy inhibitors with 2-DG may be useful clinically. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4840.