• Journal of Life Science
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• v.21 no.7
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• pp.953-960
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• 2011

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.

• Journal of Korean Neurosurgical Society
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• v.30 no.sup2
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• pp.189-196
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• 2001

Objective : We tested the hypothesis that photodynamic therapy(PDT) with Photofrin inhibits tumor invasion of U87 human glioma cells using several in vitro assay to measure tumor invasiveness. The effects of PDT on cell growth, directional migration and cell invasion were investigated. Material and Method : Tumor cells were treated with Photofrin at various doses and at a fixed optical(632nm) dose of $100mJ/cm^2$. Cytotoxicity was tested using the MTT method. Invasion assays including the matrigelartificial basement membrane barrier migration and spheroid confrontation with confocal microscopic analysis were used to study the relationship between PDT and invasiveness. Result : U87 cells showed a dose dependent cytotoxic response to increasing Photofrin dose. Data from the matrigel artificial basement membrane assay indicate that PDT inhibits the U87 cell migration dose dependently. Low doses of subcytotoxic PDT treatment, such as 2.5ug/ml Photofrin dose, also appeared to significantly inhibit migration of U87 cells(p<0.05). In co-cultures between U87 cell spheroids and brain aggregates, progressive invasion with destruction of the brain aggregate occurs. The extent of tumor cell infiltration and proportion or intact brain aggregate remaining after 24h differs in Photofrin PDT treated versus Photofrin only control, with changes suggestive of a dose-response effect. Conclusion : our data indicate that PDT with Photofrin significantly inhibits the invasiveness of U87 cells, and this inhibition is dose dependent.

• Journal of Life Science
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• v.29 no.1
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• pp.9-17
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• 2019

As tumors develop, they encounter microenvironmental stress, such as hypoxia and glucose depletion, due to poor vascular function, thereby leading to necrosis, which is observed in solid tumors. Necrotic cells are known to release cellular cytoplasmic contents, such as high mobility group box 1 (HMGB1), into the extracellular space. The release of HMGB1, a proinflammatory and tumor-promoting cytokine, plays an important role in promoting inflammation and metabolism during tumor development. Recently, HMGB1 was shown to induce the epithelial-mesenchymal transition (EMT) and metastasis. However, the underlying mechanism of the HMGB1-induced EMT, invasion, and metastasis is unclear. In this study, we showed that noninvasive breast cancer cells MCF-7 formed tightly packed, rounded spheroids and that the cells in the inner regions of a multicellular tumor spheroid (MTS), an in vitro model of a solid tumor, led to necrosis due to an insufficient supply of O2 and glucose. In addition, after 7 d of MTS culture, the EMT was induced via the transcription factor Snail. We also showed that HMGB1 receptors, including RAGE, TLR2, and TLR4, were induced by MTS culture. RAGE, TLR2, and TLR4 shRNA inhibited MTS growth, supporting the idea that RAGE/TLR2/TLR4 play critical roles in MTS growth. They also prevented MTS culture-induced Snail expression, pointing to RAGE/TLR2/TLR4-dependent Snail expression. RAGE, TLR2, and TLR4 shRNA suppressed the MTS-induced EMT. In human cancer tissues, high levels of RAGE, TLR2, and TLR4 were detected. These findings demonstrated that the HMGB-RAGE/TLR2/TLR4-Snail axis played a crucial role in the growth of the MTS and MTS culture-induced EMT.