Enhanced radiosensitivity of NSCLC cells by transducer of erbB2.1 (TOB1) through modulation of the MAPK/ERK pathway

Sun,Ke-Kang; Zhong,Ning; Yang,Yang; Zhao,Lin; Jiao,Yang

doi:10.3892/or.2013.2403

Enhanced radiosensitivity of NSCLC cells by transducer of erbB2.1 (TOB1) through modulation of the MAPK/ERK pathway

Authors:
- Ke-Kang Sun
- Ning Zhong
- Yang Yang
- Lin Zhao
- Yang Jiao
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Affiliations: Department of Gastrointestinal Surgery Division of Thoracic Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China, Key Laboratory of Radiation Biology, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
Published online on: April 12, 2013 https://doi.org/10.3892/or.2013.2403
Pages: 2385-2391

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Abstract

Transducer of erbB2.1 (TOB1) is a member of the B-cell translocation gene (BTG)/transducer of erbB2 (TOB) anti‑proliferative protein family. Previous studies have demonstrated that overexpression of TOB1 significantly enhances the radiosensitivity of breast and cervical cancer cells. However, the potential mechanisms of TOB1 are still debated. In the present study, we evaluated the effects of infrared (IR) radiation on TOB1 expression in the human lung cancer cell lines NCI-H1975 and A549 via western blot analysis. NCI-H1975 cells were transfected with TOB1 recombinant plasmid, and A549 cells were treated with TOB1-small interfering RNA (siRNA) to establish gain-of-function and loss-of‑function cell models. The effects of radiation and TOB1 overexpression and silencing on clonogenic survival, cell cycle distribution and DNA repair were assessed. Western blot analysis was performed to determine the related mechanisms. The expression levels of TOB1 were significantly induced by IR radiation. Overexpression of TOB1 abrogated radiation-induced G2/M arrest, reduced clonogenic cell survival and enhanced γ-H2AX foci in NCI-H1975 cells exposed to irradiation. TOB1-siRNA demonstrated opposite effects in A549 cells. TOB1 regulated the activation of mitogen-activated protein kinase (MAPK) and modulated the phosphorylation of p53 via activation of the MAPK/extracellular signal-regulated kinase (ERK) pathway. The findings suggest that TOB1 may be a novel molecular target of irradiation. TOB1 modulated the radiosensitivity of lung cancer cells via the MAPK/ERK signaling pathway.

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1	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Matsuda S, Kawamura-Tsuzuku J, Ohsugi M, et al: Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene. 12:705–713. 1996.PubMed/NCBI
3	Jia S and Meng A: Tob genes in development and homeostasis. Dev Dyn. 236:913–921. 2007. View Article : Google Scholar : PubMed/NCBI
4	Jiao Y, Ge CM, Meng QH, et al: Adenovirus-mediated expression of Tob1 sensitizes breast cancer cells to ionizing radiation. Acta Pharmacol Sin. 28:1628–1636. 2007. View Article : Google Scholar : PubMed/NCBI
5	Jiao Y, Sun KK, Zhao L, et al: Suppression of human lung cancer cell proliferation and metastasis in vitro by the transducer of ErbB-2.1 (TOB1). Acta Pharmacol Sin. 33:250–260. 2012. View Article : Google Scholar : PubMed/NCBI
6	Ahsan A, Hiniker SM, Davis MA, et al: Role of cell cycle in epidermal growth factor receptor inhibitor-mediated radiosensitization. Cancer Res. 69:5108–5114. 2009. View Article : Google Scholar : PubMed/NCBI
7	Wheeler DL, Dunn EF and Harari PM: Understanding resistance to EGFR inhibitors - impact on future treatment strategies. Nat Rev Clin Oncol. 7:493–507. 2010. View Article : Google Scholar : PubMed/NCBI
8	Shieh SY, Ikeda M, Taya Y, et al: DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 91:325–334. 1997. View Article : Google Scholar : PubMed/NCBI
9	Yang P: Epidemiology of lung cancer prognosis: quantity and quality of life. Methods Mol Biol. 471:469–486. 2009. View Article : Google Scholar : PubMed/NCBI
10	Molina JR, Yang P, Cassivi SD, et al: Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI
11	Ahmed KM and Li JJ: NF-kappa B-mediated adaptive resistance to ionizing radiation. Free Radic Biol Med. 44:1–13. 2008. View Article : Google Scholar : PubMed/NCBI
12	Gerber DE: EGFR inhibition in the treatment of non-small cell lung cancer. Drug Dev Res. 69:359–372. 2008. View Article : Google Scholar : PubMed/NCBI
13	Meyn RE, Munshi A, Haymach JV, et al: Receptor signaling as a regulatory mechanism of DNA repair. Radiother Oncol. 92:316–322. 2009. View Article : Google Scholar : PubMed/NCBI
14	Mahaney BL, Meek K and Lees-Miller SP: Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J. 417:639–650. 2009. View Article : Google Scholar : PubMed/NCBI
15	Morgan MA, Parsels LA, Maybaum J, et al: Improving gemcitabine-mediated radiosensitization using molecularly targeted therapy: a review. Clin Cancer Res. 14:6744–6750. 2008. View Article : Google Scholar : PubMed/NCBI
16	Chastel C, Jiricny J and Jaussi R: Activation of stress-responsive promoters by ionizing radiation for deployment in targeted gene therapy. DNA Repair (Amst). 3:201–215. 2004. View Article : Google Scholar : PubMed/NCBI
17	He HT, Fokas E, You A, et al: Siah1 proteins enhance radiosensitivity of human breast cancer cells. BMC Cancer. 10:4032010. View Article : Google Scholar : PubMed/NCBI
18	Toulany M, Kasten-Pisula U, Brammer I, et al: Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res. 12:4119–4126. 2006. View Article : Google Scholar
19	Chung EJ, Brown AP, Asano H, et al: In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 kinase. Clin Cancer Res. 15:3050–3057. 2009. View Article : Google Scholar : PubMed/NCBI
20	Li MW, Mruk DD and Cheng CY: Mitogen-activated protein kinases in male reproductive function. Trends Mol Med. 15:159–168. 2009. View Article : Google Scholar : PubMed/NCBI
21	Kim Y, Coppey M, Grossman R, et al: MAPK substrate competition integrates patterning signals in the Drosophila embryo. Curr Biol. 20:446–451. 2010. View Article : Google Scholar : PubMed/NCBI
22	Arany PR, Flanders KC, DeGraff W, et al: Absence of Smad3 confers radioprotection through modulation of ERK-MAPK in primary dermal fibroblasts. J Dermatol Sci. 48:35–42. 2007. View Article : Google Scholar : PubMed/NCBI
23	She QB, Chen N and Dong Z: ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J Biol Chem. 275:20444–20449. 2000. View Article : Google Scholar : PubMed/NCBI
24	Dumaz N and Meek DW: Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO J. 18:7002–7010. 1999. View Article : Google Scholar : PubMed/NCBI