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http://dx.doi.org/10.5352/JLS.2011.21.7.953

HMGB1 Switches Alkylating DNA Damage-Induced Apoptosis to Necrosis  

Lee, Su-Yeon (Department of Molecular Biology, College of Natural Sciences)
Jeong, Eui-Kyong (Department of Molecular Biology, College of Natural Sciences)
Jeon, Hyun-Min (Department of Molecular Biology, College of Natural Sciences)
Ju, Min-Kyung (Department of Molecular Biology, College of Natural Sciences)
Kim, Cho-Hee (Department of Molecular Biology, College of Natural Sciences)
Park, Hye-Gyeong (Nanobiotechnology Center, Pusan National University)
Kang, Ho-Sung (Department of Molecular Biology, College of Natural Sciences)
Publication Information
Journal of Life Science / v.21, no.7, 2011 , pp. 953-960 More about this Journal
Abstract
Necrosis is characterized by the cell membrane rupture and release of the cellular contents, including high-mobility group box 1 protein (HMGB1), into the extracellular microenvironment. HMGB1 acts as a transcriptional regulator in nuclei, but exerts a pro-inflammatory and tumor-promoting cytokine activity when released into the extracellular space. Its overexpression is associated with tumor progression and chemoresistance. Thus, HMGB1 acts as a clinically important molecule in tumor biology. In this study, we examined whether HMGB1 affects cell death induced by anti-cancer drugs. Here we show that HMGB1 prevented cisplatin (alkylating agent)-induced apoptosis and switched the cell fate to necrosis in MCF-7, MDA-MB231, and MDA-MB361 cells. Similar apoptosis-to-necrosis switch effects of HMGB1 were observed in cells treated with 4-HC, another alkylating agent. In contrast, HMGB1 did not exert any significant effects on docetaxel (DOC)-induced apoptosis in MCF-7 cells. We also show that cisplatin-induced apoptosis was switched to necrosis in MCF-7 multicellular tumor spheroids (MTS) that were cultured for 8 days and had necrotic cores, but DOC-induced apoptosis was prevented without the apoptosis-to-necrosis switch. Finally, the levels of RAGE, a receptor of HMGB1, were increased with extended culture of MTS. These findings demonstrate that HMGB1 switches alkylating agent-induced apoptosis to necrosis, suggesting that the strategy to prevent necrosis occurring as an undesirable action of alkylating agent-based chemotherapy should be delineated to improve the efficacy of chemotherapy for cancer.
Keywords
High-mobility group box 1 protein (HMGB1); apoptosis; necrosis; multicellular tumor spheroid;
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