Expression of ErbB2 enhances radiation-induced NF-κB activation

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 NFjB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-jB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominantnegative mutant IjB (MCF-7/ErbB2/mIjB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-jB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-jB 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-jB 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 þ IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin þ IR treatment. However, all four prosurvival proteins were downregulated by inhibition of NF-jB in MCF-7/ErbB2/mIjB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-jB response to IR, and that a specific prosurvival network downstream of NF-jB is triggered by treatments using anti-ErbB2 antibody combined with radiation.

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

“…NF-κB is a transcription factor that plays a key role in tumor radioadaptive resistance. It has been reported that DNA binding of NF-κB was activated by IR (31,32) and was regulated by various signaling cascades, e.g., the TNF-α pathway, Ras-PI3K-Akt pathway, and Ras-MAPK pathway (33)(34)(35)(36). In addition, several genes, such as the anti-apoptotic Bcl family, cyclin B1, cyclin D2, superoxide dismutases (SOD) that suppress ROS generation and HER-2, were identified as effector genes of NF-κB and these upregulated both cell proliferation and viability (21).…”

ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells

“…In various tumour specimens from cancer patients a high correlation between EGFR overexpression and NF-kB activation can be demonstrated (Tang et al, 2006;Van Laere et al, 2007). Interestingly, several pre-clinical studies using receptor-targeting strategies suggest that interference with EGFR signalling reduces NF-kB activity (Sclabas et al, 2003;Guo et al, 2004;Chinnaiyan et al, 2005;Damiano et al, 2006;Singh et al, 2007). Constitutive or deregulated NF-kB activation is observed in malignant cell types from different origin and is believed to contribute to tumourigenesis by its ability to inhibit apoptosis and to enhance cell proliferation (Keutgens et al, 2006;Pacifico and Leonardi, 2006).…”

Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-XL Bispecific Antisense Oligonucleotides in HER-2 Gene–Amplified Breast Cancer Cells

“…Whereas studies in clinical breast cancer series have documented an inverse relationship between the levels of HER-2 and Bcl-2 expression (30,31), mechanistic studies have shown that HER-2 gene transfer into MCF-7 breast cancer cells strongly up-regulates Bcl-2 and Bcl-X L expression (32,33) and that AS-mediated HER-2 down-regulation also suppresses Bcl-2 expression (23). The purpose of the present study was to assess whether HER-2 blockade by trastuzumab attenuates Bcl-2/ Bcl-X L expression and increases the susceptibility of breast cancer cells to apoptosis induction.…”