Danger Signaling Protein HMGB1 Induces a Distinct Form of Cell Death Accompanied by Formation of Giant Mitochondria
| Autor: | Marion Bergmann, Martina Keith, Julie George, Jürgen Kopitz, Anne Fassl, Otmar D. Wiestler, Georg Gdynia, Hans Walter Zentgraf, Tim Kees, Alexander N.R. Weber, Wilfried Roth, Peter Schirmacher |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Programmed cell death Necrosis Proteome Blotting Western Fluorescent Antibody Technique Mice Nude Apoptosis Mitochondrion HMGB1 Mitochondrial Proteins Mice Cell Line Tumor Tumor Cells Cultured medicine Animals Humans Cytotoxic T cell Electrophoresis Gel Two-Dimensional HMGB1 Protein Cell Proliferation Cell Nucleus Membrane Potential Mitochondrial biology Autophagy JNK Mitogen-Activated Protein Kinases Free Radical Scavengers Acetylcysteine Mitochondria Cell biology Oncology Astrocytes Cancer cell biology.protein Female medicine.symptom Glioblastoma Reactive Oxygen Species Signal Transduction |
| Zdroj: | Cancer Research. 70:8558-8568 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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 NH2-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. Cancer Res; 70(21); 8558–68. ©2010 AACR. |
| Databáze: | OpenAIRE |
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