Original Article | Published:

Antitumor Pharmacology

Growth suppression and radiosensitivity increase by HMGB1 in breast cancer

Acta Pharmacologica Sinica volume 28, pages 19571967 (2007) | Download Citation

This work was supported by the National Natural Science Foundation of China (No 30128018), the Natural Science Foundation of Jiangsu Province (No 03KJA180121), the Medical Development Foundation of Soochow University (No EE126506), and the USA National Institutes of Health (No ES013199).

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.

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Author information

Affiliations

  1. School of Radiology and Public Health, Soochow University, Suzhou 215123, China

    • Yang Jiao
    •  & Sai-jun Fan
  2. Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, Manhasset, New York 11030, USA

    • Hai-chao Wang
  3. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, Washington 20057, USA

    • Sai-jun Fan

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Corresponding author

Correspondence to Sai-jun Fan.

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DOI

https://doi.org/10.1111/j.1745-7254.2007.00669.x

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