Abstract:
AIM:HMGB1 (high-mobility group box-1) is a nuclear protein containing a consensus RB (retinoblastoma)-binding LXCXE motif. In this study, we studied the potential association of HMGB1 and RB and the in vitro and in vivo activities of HMGB1 in human breast cancer cells. METHODS:The protein-protein interaction was determined by immunoprecipitation-Western blotting and glutathione-S-transferase capture assays; cell growth and radiosensitivity were examined by cell counts, MTT assay, and clonogenic assay; cell cycle progression and apoptosis were evaluated using flow cytometry; and the antitumor activity of HMGB1 was examined with tumor xenografts in nude mice. RESULTS:HMGB1 was associated with RB via a LXCXE motif-dependent mechanism. HMGB1 enhanced the ability of RB for E2F and cyclin A transcription repression. The increased expression of HMGB1 conferred an altered phenotypes characterized by the suppression of cell growth; G1 arrest and apoptosis was induced in MCF-7 cells containing the wild-type retinoblastoma (Rb) gene, but showed no activities in BT-549 cells containing the Rb gene deletion. The HMGB1-induced apoptosis accompanied by caspase 3 activation and PARP (poly(ADP-ribose)polymerase) cleavage. HMGB1 elevated the radiosensitivity of breast cancer cells in both the MCF-7 and BT-549 cell lines. The enhanced expression of HMGB1 caused a suppression of growth of MCF-7 tumor xenografts in nude mice, while LXCXE-defective HMGB1 completely lost antitumor growth activity. CONCLUSION:HMGB1 functions as a tumor suppressor and radiosensitizer in breast cancer. A HMGB1-RB interaction is critical for the HMGB1-mediated transcriptional repression, cell growth inhibition, G1 cell cycle arrest, apoptosis induction, and tumor growth suppression, but is not required for radiosensitization. Therefore, it may be possible to design new therapies for the treatment of breast cancer that exert their effects by modulating the HMGB1 and RB regulatory pathway and HMGB1-related gene therapy.
journal_name
Acta Pharmacol Sinjournal_title
Acta pharmacologica Sinicaauthors
Jiao Y,Wang HC,Fan SJdoi
10.1111/j.1745-7254.2007.00669.xsubject
Has Abstractpub_date
2007-12-01 00:00:00pages
1957-67issue
12eissn
1671-4083issn
1745-7254journal_volume
28pub_type
杂志文章abstract:AIM:To investigate whether autologous transplantation of adult stem cells could improve post-infarcted heart function. METHODS:Bone marrow mononuclear cells (MNCs) were isolated from adult rabbits' tibias after coronary ligation. These cells were exposed to 5-azacytidine 10 micromol/L for 24 h on the third day of cult...
journal_title:Acta pharmacologica Sinica
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更新日期:2007-05-01 00:00:00
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更新日期:2007-09-01 00:00:00
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更新日期:2017-10-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2007-09-01 00:00:00
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doi:
更新日期:2003-06-01 00:00:00
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doi:
更新日期:2000-01-01 00:00:00
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更新日期:2000-11-01 00:00:00
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更新日期:2005-08-01 00:00:00