Danger Signaling Protein HMGB1 Induces a Distinct Form of Cell Death Accompanied by Formation of Giant Mitochondria

Abstract

Cells dying by necrosis release the high-mobility group box 1 (HMGB1) protein, which has immunostimulatory effects. However, little is known about the direct actions of extracellular HMGB1 protein on cancer cells. Here, we show that recombinant human HMGB1 (rhHMGB1) exerts strong cytotoxic effects on malignant tumor cells. The rhHMGB1-induced cytotoxicity depends on the presence of mitochondria and leads to fast depletion of mitochondrial DNA, severe damage of the mitochondrial proteome by toxic malondialdehyde adducts, and formation of giant mitochondria. The formation of giant mitochondria is independent of direct nuclear signaling events, because giant mitochondria are also observed in cytoplasts lacking nuclei. Further, the reactive oxygen species scavenger N-acetylcysteine as well as c-Jun NH 2 -terminal kinase blockade inhibited the cytotoxic effect of rhHMGB1. Importantly, glioblastoma cells, but not normal astrocytes, were highly susceptible to rhHMGB1-induced cell death. Systemic treatment with rhHMGB1 results in significant growth inhibition of xenografted tumors in vivo. In summary, rhHMGB1 induces a distinct form of cell death in cancer cells, which differs from the known forms of apoptosis, autophagy, and senescence, possibly representing an important novel mechanism of specialized necrosis. Further, our findings suggest that rhHMGB1 may offer therapeutic applications in treatment of patients with malignant brain tumors.

Complementary Induction of Immunogenic Cell Death by Oncolytic Parvovirus H-1PV and Gemcitabine in Pancreatic Cancer

“…Yet it failed to induce release of any immunogenic determinant besides HMGB1, disproving HMGB1 bias as a consequence of the preferential death modality. Levels of accumulated HMGB1 in PDAC H-1PV cultures were the same as those recently shown to induce mitochondrial swelling and death in glioblastoma and carcinoma cell lines (66). We thus suspected that released HMGB1 itself might be responsible for ICD-silent killing of PDAC cells.…”

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

“…Because of the decreased size of miR-218-expressing orthotopic lesions, we investigated the role of nonapoptotic cell death downstream of TMZ treatment. Loss of nuclear high-mobility group protein B1 (HMBG1) stain is a marker for autophagic, tumor cytolytic, or necrotic cell death (23)(24)(25)(26), and we observed a significant reduction in nuclear HMGB1 staining in miR-218-expressing, TMZ-treated tumors in both orthotopic models ( identify increased nonapoptotic cell death as a mechanism to explain the reduced tumor growth in miR-218-expressing tumors treated with TMZ. A cohort of mice with orthotopic U87-SCR and U87-218 tumors was treated with DMSO or TMZ and monitored until they exhibited evidence of neurological deficits, at which time they were killed.…”

HMGB1 in health and disease

“…apoptosis and necrosis) and tissue injury (Kikuchi et al, 2009a). In addition, HMGB1 can induce a special form of cell death in glioblastoma cells, which lack the typical features of apoptosis, autophagy, or classic necrosis (Gdynia et al, 2010). Exogenous HMGB1 can enter host mitochondria by an endocytosis-independent mechanism and result in the formation of vacuolated giant mitochondria and a rapid depletion of mitochondrial DNA (Gdynia et al, 2010).…”

“…In addition, HMGB1 can induce a special form of cell death in glioblastoma cells, which lack the typical features of apoptosis, autophagy, or classic necrosis (Gdynia et al, 2010). Exogenous HMGB1 can enter host mitochondria by an endocytosis-independent mechanism and result in the formation of vacuolated giant mitochondria and a rapid depletion of mitochondrial DNA (Gdynia et al, 2010). Exogenous HMGB1 can rhHMGB1 localizes to the mitochondria and induces the formation of giant mitochondria, which is independent of TLR2, TLR4, or RAGE signaling (Gdynia et al, 2010).…”