Abstract
Breast cancer is a common malignancy among women and is associated with poor 5-year survival rates. Gene radiotherapy, that is, gene therapy combined with radiotherapy, has been extensively studied as a new mode of therapy, but most studies have assessed only one gene. Here, we inserted two anti-oncogenes, ING4 (inhibitor of growth family member 4) and interleukin-24 (IL-24), in the same bicistronic adenovirus vector and explored the effect of dual-gene therapy combined with radiotherapy on breast cancer cells. Flow cytometry assays showed that adenovirus-mediated ING4 and IL-24 expression could suppress growth, promote apoptosis and induce G2/M cell-cycle arrest in MDA-MB-231 cells. Moreover, animal model studies demonstrated that the combination of ING4/IL-24 gene therapy and radiotherapy significantly suppressed cell proliferation and inhibited tumor growth (P<0.05). Mechanistically, the pro-apoptotic response likely involved the upregulation of Bax and Caspase-3 and the downregulation of Bcl-2. Thus, this study indicates that the co-expression of the two anti-oncogenes, ING4 and IL-24, could significantly promote radiotherapy sensitivity in MDA-MB-231 breast cancer cells.
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
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.
Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML . Dose locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000; 18: 1220–1229.
Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997; 337: 949–955.
Paszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E . Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 1998; 16: 2625–2631.
Early Breast Cancer Trialists’ Collaborative Group.. Effects of radiotherapy and surgery in early breast cancer-an overview of the randomized trials. New Eng J Med 1995; 33: 1444–1455.
Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009; 326: 818–823.
Naldini LA . Comeback for gene therapy. Science 2009; 326: 805–806.
Dutreix M, Cosset JM, Sun JS . Molecular therapy in support to radiotherapy. Mutat Res 2010; 704: 182–189.
Shiseki M, Nagashima M, Pedeux RM, Kitahama-Shiseki M, Miura K, Okamura S et al. p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res 2003; 63: 2373–2378.
Zhang X, Xu LS, Wang ZQ, Wang KS, Li N, Cheng ZH et al. ING4 induces G2/M cell cycle arrest and enhances the chemosensitivity to DNA-damage agents in HepG2 cells. FEBS Lett 2004; 570: 7–12.
Xie Y, Zhang H, Sheng W, Xiang J, Ye Z, Yang J . Adenovirus-mediated ING4 expression suppresses lung carcinoma cell growth via induction of cell cycle alteration and apoptosis and inhibition of tumor invasion and angiogenesis. Cancer Lett 2008; 271: 105–116.
Cai L, Li X, Zheng S, Wang Y, Wang Y, Li H et al. Inhibitor of growth 4 is involved in melanomagenesis and induces growth suppression and apoptosis in melanoma cell line M14. Melanoma Res 2009; 19: 1–7.
Xie YF, Sheng W, Xiang J, Zhang H, Ye Z, Yang J . Adenovirus-mediated ING4 expression suppresses pancreatic carcinoma cell growth via induction of cell-cycle alteration, apoptosis, and inhibition of tumor angiogenesis. Cancer Biother Radiopharm 2009; 24: 261–269.
Colla S, Tagliaferri S, Morandi F, Lunghi P, Donofrio G, Martorana D et al. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 alpha (HIF-1alpha) activity: involvement in myeloma-induced angiogenesis. Blood 2007; 110: 4464–4475.
Li Z, Xie Y, Sheng W, Miao J, Xiang J, Yang J . Tumor-suppressive effect of adenovirus-mediated inhibitor of growth 4 gene transfer in breast carcinoma cells in vitro and in vivo. Cancer Biother Radiopharm 2010; 25: 427–437.
Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB . Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995; 11: 2477–2486.
Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Lebedeva IV, Dent P et al. MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine. Cytokine Growth Factor Rev 2003; 14: 35–51.
Fisher PB . Is mda-7/IL-24 a ‘magic bullet’ for cancer? Cancer Res 2005; 65: 10128–10138.
Sheng WH, Xie YF, Miao JC, Gu FB, Shan YB, Liu TL et al. The anti-tumor effect by adenovirus-mediated ING4 and IL-24 co-expression on hepatocellular carcinoma in vitro. Chin J Microbiol Immunol 2010; 30: 695–703.
Zhu Y, Lv H, Xie Y, Sheng W, Xiang J, Yang J . Enhanced tumor suppression by an ING4/IL-24 bicistronic adenovirus-mediated gene cotransfer in human non-small cell lung cancer cells. Cancer Gene Ther 2011; 18: 627–636.
Keall PJ, Lammering G, Lin PS, Winter DS, Chung TD, Mohan R et al. Tumor control probability predictions for genetic radiotherapy. Int J Radiat Oncol Biol Phys 2003; 57: 255–263.
Zeng M, Cerniglia GJ, Eck SL, Stevens CW . High-efficiency stable gene transfer of adenovirus into mammalian cells using ionizing radiation. Hum Gene Ther 1997; 8: 1025–1032.
Zhao YZ, Wang J, Wang Q, Mu CJ . The mechanisms of inter-effect about gene therapy and radiotherapy to tumor and the prospect of therapeutic alliance. Int J Radiat Med Nucl Med 2006; 30: 250–253.
Wilson DR . Viral-mediated gene transfer for cancer treatment. Curr Pharm Biotechnol 2002; 3: 151–164.
Pei Z, Chu L, Zou W, Zhang Z, Qiu S, Qi R et al. An oncolytic adenoviral vector of Smac increases antitumor activity of TRAIL against HCC in human cells and in mice. Hepatology 2004; 39: 1371–1381.
Shen Y, Muramatsu SI, Ikeguchi K, Fujimoto KI, Fan DS, Ogawa M et al. Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic-L-amino-acid decarboxylase, and GTP cyclohydrolase I for gene therapy of Parkinson's disease. Hum Gene Ther 2000; 11: 1509–1519.
Ngoi SM, Chien AC, Lee CG . Exploiting internal ribosome entry sites in gene therapy vector design. Curr Gene Ther 2004; 4: 15–31.
Fotedar R, Diederich L, Fotedar A . Apoptosis and the cell cycle. Prog Cell Cycle Res 1996; 2: 147–163.
Pawlik TM, Keyomarsi K . Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 2004; 59: 928–942.
Danial NN, Korsmeyer SJ . Cell death: critical control points. Cell 2004; 116: 205–219.
Acknowledgements
The current research was supported by the National Natural Science Foundation of China (No. 81001016; 81101909).
Ethical approval
Data collection was approved by the Soochow University Review Board and Ethics Committee.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Zhao, Y., Li, Z., Sheng, W. et al. Radiosensitivity by ING4–IL-24 bicistronic adenovirus-mediated gene cotransfer on human breast cancer cells. Cancer Gene Ther 20, 38–45 (2013). https://doi.org/10.1038/cgt.2012.82
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cgt.2012.82
Keywords
This article is cited by
-
Interleukin-24-mediated antitumor effects against human glioblastoma via upregulation of P38 MAPK and endogenous TRAIL-induced apoptosis and LC3-II activation-dependent autophagy
BMC Cancer (2023)
-
INGs are potential drug targets for cancer
Journal of Cancer Research and Clinical Oncology (2017)
-
Combinatorial strategies based on CRAd-IL24 and CRAd-ING4 virotherapy with anti-angiogenesis treatment for ovarian cancer
Journal of Ovarian Research (2016)
-
Inhibitor of growth-4 is a potential target for cancer therapy
Tumor Biology (2016)
-
Enhanced antitumor efficacy of a novel oncolytic adenovirus combined with temozolomide in the treatment of melanoma in vivo
Journal of Cancer Research and Clinical Oncology (2015)