Metabolic and therapeutic stress can simultaneously provoke both adaptive and apoptotic responses in cancer cells. The sum of these programmed signals determines the fate of the cell: cell death or cell survival. As the catalogue of defects in pathways that control apoptosis in human tumors is expanding, understanding the significance of the alternative stress fate, autophagy, has become increasingly important. High-mobility group box 1 protein (HMGB1) is a highly conserved nuclear protein, acting as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets. In addition to its intranuclear roles, HMGB1 was also discovered recently to function as an extracellular signaling molecule during inflammation, cell differentiation, cell migration, and tumor metastasis. Ethyl pyruvate was first identified as an experimental agent that ameliorated inflammation, significantly reducing circulating levels of HMGB1 in animals with sepsis. Similarly, glycyrrhizin was identified as a direct small-molecule inhibitor of HMGB1 release and activity. To determine whether inhibition of HMGB1 release sensitizes cancer cells to chemotherapy, we pretreated cell with ethyl pyruvate or glycyrrhizin. These inhibitors attenuated melphalan-induced HMGB1 release. Moreover, inhibition of HMGB1 decreased autophagy by microtubule-associated protein 1 light chain 3 (LC3) puncta and LC3-II/p62 levels assay, and increased apoptosis by flow cytometry and cleaved-poly (ADP-ribose) polymerase (PARP) assays in Panc2.03 and HCT116 tumor cells when treated with chemotherapy. To further characterize the role of HMGB1 release in cancer cells following chemotherapy, a target-specific short hairpin RNA (shRNA) to HMGB1 was transferred into Panc2.03 and HCT116 tumor cells. Transfection of HMGB1-shRNA led to a significant decrease in HMGB1 protein as well as release in these cells. Depletion of HMGB1 by shRNA in these cells decreased autophagy and rendered them significantly more sensitive to melphalan-induced apoptotic cell death. Thust HMGB1 release links autophagy and apoptosis, and serves as a potential drug target for therapeutic intervention.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

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 4854.

©2010 American Association for Cancer Research
2010