Expression of ErbB2 enhances radiation-induced NF-κB activation

Guozheng Guo, Tieli Wang, Qian Gao, Daniel Tamae, Patty Wong, Tammy Chen, Wei Chung Chen, John E. Shively, Jeffery Y C Wong, Jian-Jian Li

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Her-2/neu (ErbB2) oncogene, the second member of the epidermal growth factor receptor (EGFR) family, encodes a transmembrane tyrosine kinase receptor in Her-2-positive tumors. Accumulating evidences demonstrate that signaling networks activated by EGFR and transcription factor NF-κB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-κB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominant-negative mutant IκB (MCF-7/ErbB2/mIκB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-κB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-κB regulation, basal and IR-induced Akt, a kinase downstream of ErbB2, was activated in MCF-7/ ErbB2 cells and inhibited by Herceptin. To identify specific genes affected by ErbB2-mediated NF-κB activation, a group of IR-responsive elements Cyclin B1, Cyclin D1, Bcl-2, Bcl/XL, BAD and BAX were evaluated. Basal levels of prosurvival elements Cyclin B1, Cyclin D1, Bcl-2 and Bcl/XL but not apoptotic BAD and BAX were upregulated in MCF-7/ErbB2 cells with striking enhancements in Bcl-2 and Bcl/XL. IR further induced Cyclin B1 and Cyclin D1 expression that was reduced by Herceptin. Bcl-2 kept a high steady level after Herceptin+IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin+IR treatment. However, all four prosurvival proteins were down-regulated by inhibition of NF-κB in MCF-7/ErbB2/mIκB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-κB response to IR, and that a specific prosurvival network downstream of NF-κB is triggered by treatments using anti-ErbB2 antibody combined with radiation.

Original languageEnglish (US)
Pages (from-to)535-545
Number of pages11
JournalOncogene
Volume23
Issue number2
DOIs
StatePublished - Jan 15 2004
Externally publishedYes

Fingerprint

erbB-2 Genes
MCF-7 Cells
Ionizing Radiation
Radiation
Cyclin B1
Cyclin D1
Epidermal Growth Factor Receptor
Anti-Idiotypic Antibodies
Receptor Protein-Tyrosine Kinases
Oncogenes
Transfection
Transcription Factors
Phosphotransferases
Trastuzumab
Breast Neoplasms

Keywords

  • Breast cancer
  • ErbB2
  • NF-κB
  • Radioresistance

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Guo, G., Wang, T., Gao, Q., Tamae, D., Wong, P., Chen, T., ... Li, J-J. (2004). Expression of ErbB2 enhances radiation-induced NF-κB activation. Oncogene, 23(2), 535-545. https://doi.org/10.1038/sj.onc.1207149

Expression of ErbB2 enhances radiation-induced NF-κB activation. / Guo, Guozheng; Wang, Tieli; Gao, Qian; Tamae, Daniel; Wong, Patty; Chen, Tammy; Chen, Wei Chung; Shively, John E.; Wong, Jeffery Y C; Li, Jian-Jian.

In: Oncogene, Vol. 23, No. 2, 15.01.2004, p. 535-545.

Research output: Contribution to journalArticle

Guo, G, Wang, T, Gao, Q, Tamae, D, Wong, P, Chen, T, Chen, WC, Shively, JE, Wong, JYC & Li, J-J 2004, 'Expression of ErbB2 enhances radiation-induced NF-κB activation', Oncogene, vol. 23, no. 2, pp. 535-545. https://doi.org/10.1038/sj.onc.1207149
Guo G, Wang T, Gao Q, Tamae D, Wong P, Chen T et al. Expression of ErbB2 enhances radiation-induced NF-κB activation. Oncogene. 2004 Jan 15;23(2):535-545. https://doi.org/10.1038/sj.onc.1207149
Guo, Guozheng ; Wang, Tieli ; Gao, Qian ; Tamae, Daniel ; Wong, Patty ; Chen, Tammy ; Chen, Wei Chung ; Shively, John E. ; Wong, Jeffery Y C ; Li, Jian-Jian. / Expression of ErbB2 enhances radiation-induced NF-κB activation. In: Oncogene. 2004 ; Vol. 23, No. 2. pp. 535-545.
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N2 - Her-2/neu (ErbB2) oncogene, the second member of the epidermal growth factor receptor (EGFR) family, encodes a transmembrane tyrosine kinase receptor in Her-2-positive tumors. Accumulating evidences demonstrate that signaling networks activated by EGFR and transcription factor NF-κB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-κB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominant-negative mutant IκB (MCF-7/ErbB2/mIκB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-κB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-κB regulation, basal and IR-induced Akt, a kinase downstream of ErbB2, was activated in MCF-7/ ErbB2 cells and inhibited by Herceptin. To identify specific genes affected by ErbB2-mediated NF-κB activation, a group of IR-responsive elements Cyclin B1, Cyclin D1, Bcl-2, Bcl/XL, BAD and BAX were evaluated. Basal levels of prosurvival elements Cyclin B1, Cyclin D1, Bcl-2 and Bcl/XL but not apoptotic BAD and BAX were upregulated in MCF-7/ErbB2 cells with striking enhancements in Bcl-2 and Bcl/XL. IR further induced Cyclin B1 and Cyclin D1 expression that was reduced by Herceptin. Bcl-2 kept a high steady level after Herceptin+IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin+IR treatment. However, all four prosurvival proteins were down-regulated by inhibition of NF-κB in MCF-7/ErbB2/mIκB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-κB response to IR, and that a specific prosurvival network downstream of NF-κB is triggered by treatments using anti-ErbB2 antibody combined with radiation.

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