Abstract 2144: Characterization of HMGB1-induced cell death in colon carcinoma cells

Abstract

Abstract The danger protein HMGB1 induces a distinct form of cell death in cancer cells which is different from classical necrosis, apoptosis, autophagy, or senescence. Interestingly, colon carcinoma cells are less sensitive for the cytotoxic activity of HMGB1 than other types of cancer cells. The aim of this study was to characterize the molecular and metabolic pathways regulating the susceptibility to HMGB1 in colorectal carcinoma. Stable ectopic over-expression of HMGB1 inhibited significantly the proliferation of colon carcinoma cells. Treatment of cells with recombinant human (rh) HMGB1 induced significant cytotoxicity in a concentration range of 80 – 200 nM. Cancer cells depleted of mitochondrial DNA were less susceptible to the cytotoxic effects of rhHMGB1. In ATP luciferase assays, after 72 h of incubation with rhHMGB1 a significant depletion of intracellular ATP was observed, paralleled by the formation of giant mitochondria. RhHMGB1 modulated the specific activity of the mitochondrial respiratory enzymes and the electron flux in the electron transport chain in a dose-dependent manner. Interestingly, addition of NAD+, L-pyruvate, or ATP did not protect the cells from rhHMGB1-induced cell death. RhHMGB1-induced mitochondrial and metabolic events were further characterized by tracking radioactive glucose and pyruvate isotopes. In summary, the HMGB1 protein induces a novel form of cell death in diverse types of cancer cells. In colon cancer cells, HMGB1 modulates the activity of the mitochondrial respiratory enzymes leading to a change in glycolytic flux and a strong depletion of intracellular ATP. These observations implicate a new functional link between the HMGB1 protein and mitochondrial respiratory regulation as well as glycolysis activity in cancer cells. 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 2144. doi:10.1158/1538-7445.AM2011-2144