期刊
EUROPEAN JOURNAL OF CANCER
卷 49, 期 3, 页码 741-751出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2012.09.016
关键词
HMGB1; Necrosis; Apoptosis; TLR4; RAGE
类别
资金
- Japan Society for the Promotion of Science, Japan
- Ministry of Health, Labour and Welfare, Japan
- Grants-in-Aid for Scientific Research [24590450, 25670177, 23659188] Funding Source: KAKEN
The role of the high mobility group box 1 (HMGB1) protein in chemotherapy-induced cell death was examined. CT26 mouse colon cancer cells were treated with trichostatin A (TSA; apoptosis inducer) or doxorubicin (DXR; necrosis inducer). DXR increased HMGB1 concentration in CT26 cell culture medium, whereas TSA did not. In a CT26 bilateral subcutaneous tumour model, DXR or TSA was injected in a single tumour. After injection, serum HMGB1 concentration in DXR-treated mice was 10 times higher than that in TSA-treated mice. After DXR treatment, the contralateral and remnant tumours showed more pronounced growth than did those treated with TSA. In mouse models, lung and liver metastasis was enhanced by DXR but not by TSA. DXR-enhanced metastasis was abrogated by anti-HMGB1 antibody treatment. In a cancer dormancy model, DXR induced regrowth of quiescent CT26 cells. HMGB1 induced tumour necrosis factor-a secretion via Toll-like receptor (TLR) 4 in U937 monocytes; however, HMGB1 decreased the number of U937 cells, resulting in restriction of immune activation via receptor for advanced glycation endproducts (RAGE). RAGE showed a more pronounced effect on nuclear factor kappa B activation than did TLR4 in CT26 cells. These findings suggest that HMGB1 released from necrotic cancer cells treated with a necrosis inducer enhances regrowth and metastasis of remnant cancer cells via RAGE activation. (C) 2012 Elsevier Ltd. All rights reserved.
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