Abstract
Breast cancer is one of the most prevalent cancers worldwide. Moreover, despite advances in antineoplastic therapies, induction of tumor cell death without off-target cytotoxicity remains a challenge. However, recent developments in localized radiotherapy and gene therapy have provided an opportunity to explore the potential for these strategies to be additive for the induction of cell death in tumor cells. Here, a novel adenoviral shuttle vector containing the proapoptotic gene Smac under the control of the ionizing radiation (IR)-induced Egr1 promoter was constructed. Following the transient transfection of the construct into MCF-7 and MDA-MB-435 breast cancer cell lines, acute and abundant expression of Smac was observed in response to IR treatment. Further analysis confirmed that the induction of Smac expression resulted in a decrease in cell viability, a slower rate of cell growth, a higher level of apoptosis and altered cell cycle progression. Using a clonogenic assay, IR-induced Smac expression was also found to significantly sensitize Smac-expressing cells to radiation-induced cell death. Taken together, these data suggest that Smac expression driven by the Egr1 promoter has the potential to serve as a radiotherapy-dependent gene therapy agent.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ et al. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 2011; 378: 1461–1484.
Dachs GU, Dougherty GJ, Stratford IJ, Chaplin DJ . Targeting gene therapy to cancer: a review. Oncol Res 1997; 9: 313–325.
Weichselbaum RR, Hallahan DE, Sukhatme VP, Kufe DW . Gene therapy targeted by ionizing radiation. Int J Radiat Oncol Biol Phys 1992; 24: 565–567.
Hu Y, Ouyang W, Wu F, Cao CH, Wang K, Liao ZK et al. Enhanced radiosensitivity of SW480 cells via TRAIL up-regulation mediated by Egr-1 promoter. Oncol Rep 2009; 22: 765–771.
Li Y, Guo C, Wang Z, Gong P, Sun Z, Gong S et al. Enhanced effects of TRAIL-endostatin-based double-gene-radiotherapy on suppressing growth, promoting apoptosis and inducing cell cycle arrest in vascular endothelial cells. J Huazhong Univ Sci Technolog Med Sci 2012; 32: 167–172.
Li YB, Guo CX, Wang ZC, Dong LH, Guan F, Liu Y et al. Radiosensitization of breast cancer cells by TRAIL-endostatin-targeting gene therapy. Neoplasma 2013; 60: 613–619.
Vaux DL, Silke J . Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun 2003; 304: 499–504.
Toulany M, Dittmann K, Krüger M, Baumann M, Rodemann HP . Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway. Radiother Oncol 2005; 76: 143–150.
Toulany M, Schickfluss TA, Eicheler W, Kehlbach R, Schittek B, Rodemann HP et al. Impact of oncogenic K-RAS on YB-1 phosphorylation induced by ionizing radiation. Breast Cancer Res 2011; 13: R28.
Yang TJ, Ho AY . Radiation therapy in the management of breast cancer. Surg Clin North Am 2013; 93: 455–471.
Qin S, Yang C, Li S, Xu C, Zhao Y, Ren H et al. Smac: its role in apoptosis induction and use in lung cancer diagnosis and treatment. Cancer Lett 2012; 318: 9–13.
Martinez-Ruiz G, Maldonado V, Ceballos-Cancino G, Grajeda JP, Melendez-Zajgla J . Role of Smac/DIABLO in cancer progression. J Exp Clin Cancer Res 2008; 27: 48.
Marignol L, Coffey M, Hollywood D, Lawler M . Radiation to control transgene expression in tumors. Cancer Biol Ther 2007; 6: 1005–1012.
Acknowledgements
We thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript. This project was supported by the National Natural Science Foundation of China (Grant No. 30970681).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Cancer Gene Therapy website
Rights and permissions
About this article
Cite this article
Li, ZL., Liang, S., Wang, ZC. et al. Expression of Smac induced by the Egr1 promoter enhances the radiosensitivity of breast cancer cells. Cancer Gene Ther 21, 142–149 (2014). https://doi.org/10.1038/cgt.2014.9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cgt.2014.9