Abstract 2725: 2-Deoxyglucose inhibits KSHV replication under normoxic conditions
Authors: Leung Howard J. , Duran Margarita , Kurtoglu Metin , Lampidis Theodore J. , Mesri Enrique A. 
Published: June 2012

BACKGROUND: Cancer cells are more glycolytic than normal cells and thereby take up more glucose, as demonstrated by the positron emission tomography (PET) scan. This can be exploited for cancer therapy using glycolytic inhibitors such as 2-deoxy-D-glucose (2DG). Due to its similarity to mannose, 2DG also interferes with N-linked glycosylation resulting in an unfolded protein response (UPR), which slows growth of tumors. Additionally, 2DG inhibits productive infection of enveloped viruses, e.g. herpesviruses, due to its interference with glycosylation of viral proteins. Kaposi's sarcoma (KS) is a cancer that is caused by infection of a gammaherpesvirus; KS might be particularly vulnerable to 2DG, given the chemical's properties as both an anti-cancer and an anti-viral agent. We are investigating the mechanisms and their resulting effects by which cell culture models for KS are sensitive to 2DG treatment in the context of viral replication.

DESIGN: Two models of herpesvirus infection were used for 2DG treatment in vitro: KS-associated herpesvirus (KSHV) and murine herpesvirus-68 (MHV-68). Human embryonic kidney cells latently infected with a recombinant KSHV genome (HEK293rKSHV.219) were induced to lytic reactivation upon addition of sodium butyrate. Murine embryonic fibroblasts were infected de novo with MHV-68 to cause lytic replication. In each model, cells were treated with nontoxic doses of 2DG. RNA and protein levels were measured at 24 hours treatment; cell proliferation and viral copy number were measured at 72 hours.

RESULTS: In two different models of gammaherpesvirus infection we find that 2DG inhibits expression of early and late viral lytic genes, as well as interferes with the ability of the host to produce infectious virions. While 2DG is used at nontoxic concentrations, the compound inhibits cell proliferation. Treatment with inhibitors of glycolysis–but not glycosylation–does not significantly decrease viral copy number or infectious particles released from infected cells. Furthermore, 2DG is correlated with UPR induction by the phosphorylation of the alpha subunit of eukaryotic translation initiation factor-2 as well as up-regulation of the endoplasmic reticulum (ER) chaperone glucose-regulated protein-78 at both the RNA and protein levels.

CONCLUSION: Overall, these results indicate that a major mechanism by which 2DG inhibits viral replication might be through ER stress/UPR. Furthermore, 2DG action takes place early in the viral lytic cycle, preventing the induction of viral genes, which correlates to the inability to produce mature viral particles. These data suggest that 2DG may be clinically beneficial in the treatment of herpesvirus-induced cancers.

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 2725. doi:10.1158/1538-7445.AM2011-2725