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Expression of ErbB2 enhances radiation-induced NF-κB activation

Oncogene volume 23, pages 535–545 (2004)Cite this article

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 downregulated 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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Abbreviations

IR:

ionizing radiation

NF-κB:

nuclear factor kappaB

ROS:

reactive oxygen species

TNF:

tumor necrosis factor

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Acknowledgements

We thank Dr Dennis J Slamon at the University of California Los Angeles for kindly providing MCF-7/ErbB2 and vector control cells; Dr Nancy Colburn at the National Cancer Institute for providing mutant IκB plasmids; Dr David Colcher at City of Hope National Medical Center for insightful discussion and reviewing the manuscript. This work was partially supported by an International Union Against Cancer Fellowship (GG), The Beckman Fellowship (TW) and the City of Hope Summer Research Program (TC and WCC).

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Author notes

  1. Guozheng Guo

    Present address: Deptartment of Radiation Medicine, the 4th Military Medical University, Xian, 710032, P.R. China

  2. Guozheng Guo and Tieli Wang: These authors have contributed equally to this work

Authors and Affiliations

  1. Division of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, 91010, CA, USA

    Guozheng Guo, Tieli Wang, Daniel Tamae, Patty Wong, Tammy Chen, Wei-Chung Chen, Jeffery YC Wong & Jian Jian Li

  2. Life Science Group, Bio-Rad Laboratories, 2000 Alfred Nobel Drive, Hercules, 94547, CA, USA

    Qian Gao

  3. Division of Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, 91010, CA, USA

    John E Shively

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Guo, G., Wang, T., Gao, Q. et al. Expression of ErbB2 enhances radiation-induced NF-κB activation. Oncogene 23, 535–545 (2004). https://doi.org/10.1038/sj.onc.1207149

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