Iodine-131 induces apoptosis in HTori-3 human thyrocyte cell line and G2/M phase arrest in a p53-independent pathway

Zhang,Weixiao; Gao,Rui; Yu,Yan; Guo,Kun; Hou,Peng; Yu,Mingqi; Liu,Yan; Yang,Aimin

doi:10.3892/mmr.2014.3096

Iodine-131 induces apoptosis in HTori-3 human thyrocyte cell line and G2/M phase arrest in a p53-independent pathway

Authors:
- Weixiao Zhang
- Rui Gao
- Yan Yu
- Kun Guo
- Peng Hou
- Mingqi Yu
- Yan Liu
- Aimin Yang
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Affiliations: Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China, Department of Public Health, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China, Endocrinology Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China
Published online on: December 16, 2014 https://doi.org/10.3892/mmr.2014.3096
Pages: 3148-3154

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Abstract

Iodine‑131 is known to destroy residual thyroid tissue following surgical resection of differentiated thyroid carcinoma and is widely used to treat hyperthyroidism. However, the mechanism by which iodine‑131 induces apoptosis and cell cycle arrest in the human thyrocyte cell line, Htori‑3, remains to be elucidated. In the present study, the cytotoxic effect of iodine‑131 on the HTori‑3 cell line and the underlying mechanism of iodine‑131‑induced cell apoptosis were investigated. Cell viability was analyzed using an MTT assay, while cell apoptosis and cell cycle arrest were determined using flow cytometry. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses were performed to determine the changes in the expression levels of p53, B‑cell lymphoma 2 (Bcl‑2), Fas and growth arrest and DNA damage‑inducible 45 (GADD45), following iodine‑131 treatment. The results demonstrated that iodine‑131 may inhibit HTori‑3 cell growth via cell apoptosis and G2/M phase arrest in a time‑ and dose‑dependent manner. The iodine‑131 dose required for 50% growth inhibition of HTori‑3 cell viability 48 h after treatment was 27.75±2.22 MBq/ml. Upregulation of Fas and downregulation of Bcl‑2 expression levels were observed following iodine‑131 treatment. The results of RT‑qPCR revealed an increase in the GADD45 mRNA expression following HTori‑3 cell exposure to iodine‑131. Notably, the mRNA and protein expression levels of p53 were not altered following iodine‑131 treatment. In conclusion, iodine‑131 may induce apoptosis in HTori‑3 cells by downregulating the expression of Bcl‑2 and upregulating the expression of Fas. In addition, iodine‑131 may upregulate GADD45 mRNA expression in HTori‑3 cells, resulting in G2/M phase arrest in a p53‑independent pathway.

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1	Friesen C, Lubatschofski A, Kotzerke J, Buchmann I, Reske SN and Debatin KM: Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells. Eur J Nucl Med Mol Imaging. 30:1251–1261. 2003. View Article : Google Scholar : PubMed/NCBI
2	Wang C, Wang J, Jiang H, Zhu M, Chen B and Bao W: In vitro study on apoptosis induced by strontium-89 in human breast carcinoma cell line. J Biomed Biotechnol. 2011:5414872011. View Article : Google Scholar : PubMed/NCBI
3	Sawka AM, Thephamongkhol K, Brouwers M, Thabane L, Browman G and Gerstein HC: Clinical review 170: A systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab. 89:3668–3676. 2004. View Article : Google Scholar : PubMed/NCBI
4	Bogazzi F, Giovannetti C, Fessehatsion R, et al: Impact of lithium on efficacy of radioactive iodine therapy for Graves’ disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal. J Clin Endocrinol Metab. 95:201–208. 2010. View Article : Google Scholar
5	Eriksson D, Blomberg J, Lindgren T, Löfroth PO, et al: Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells. Cancer Biother Radiopharm. 23:541–549. 2008. View Article : Google Scholar : PubMed/NCBI
6	Marx K, Moka D, Schomäcker K, et al: Cell death induced by ¹³¹I in a differentiated thyroid carcinoma cell line in vitro: necrosis or apoptosis? Nucl Med Commun. 27:353–358. 2006. View Article : Google Scholar : PubMed/NCBI
7	Reinhardt HC and Schumacher B: The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 28:128–136. 2012. View Article : Google Scholar : PubMed/NCBI
8	Feng Z and Levine AJ: The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol. 20:427–434. 2010. View Article : Google Scholar : PubMed/NCBI
9	Jin S and Levine AJ: The p53 functional circuit. J Cell Sci. 114:4139–4140. 2001.PubMed/NCBI
10	Brunelle JK and Letai A: Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 122:437–441. 2009. View Article : Google Scholar : PubMed/NCBI
11	Shi L, Chen J, Yang J, Pan T, Zhang S and Wang Z: MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res. 1352:255–264. 2010. View Article : Google Scholar : PubMed/NCBI
12	Villa-Morales M, González-Gugel E, Shahbazi MN, Santos J and Fernández-Piqueras J: Modulation of the Fas-apoptosis-signalling pathway by functional polymorphisms at Fas, FasL and Fadd and their implication in T-cell lymphoblastic lymphoma susceptibility. Carcinogenesis. 31:2165–2171. 2010. View Article : Google Scholar : PubMed/NCBI
13	Ji J, Tian Y, Ji S, Zhang L, Zhu Y and Lu X: Ionizing radiation induces cell cycle G1 arrest and tumor suppressor gene P16, P21, P27 expression in keloid fibroblasts. Int J Radiat Oncol. 87(Suppl): S6292013. View Article : Google Scholar
14	Niehrs C and Schäfer A: Active DNA demethylation by Gadd45 and DNA repair. Trends Cell Biol. 22:220–227. 2012. View Article : Google Scholar : PubMed/NCBI
15	Pilli T, Prasad KV, Jayarama S, Pacini F and Prabhakar BS: Potential utility and limitations of thyroid cancer cell lines as models for studying thyroid cancer. Thyroid. 19:1333–1342. 2009. View Article : Google Scholar : PubMed/NCBI
16	Caudill CM, Zhu Z, Ciampi R, Stringer JR and Nikiforov YE: Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to γ-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation. J Clin Endocrinol Metab. 90:2364–2369. 2005. View Article : Google Scholar : PubMed/NCBI
17	Moore S, Stanley FK and Goodarzi AA: The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation - no simple task. DNA Repair (Amst). 17:64–73. 2014. View Article : Google Scholar
18	Reisz JA, Bansal N, Qian J, Zhao W and Furdui CM: Effects of ionizing radiation on biological molecules - mechanisms of damage and emerging methods of detection. Antioxid Redox Signal. 10:260–292. 2014. View Article : Google Scholar
19	Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
20	Villa-Morales M and Fernández-Piqueras J: Targeting the Fas/FasL signaling pathway in cancer therapy. Expert Opin Ther Targets. 16:85–101. 2012. View Article : Google Scholar : PubMed/NCBI
21	Koster R, Timmer-Bosscha H, Bischoff R, Gietema JA and de Jong S: Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death Dis. 2:e1482011. View Article : Google Scholar : PubMed/NCBI
22	Cory S and Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
23	Sak A, Wurm R, Elo B, et al: Increased radiation-induced apoptosis and altered cell cycle progression of human lung cancer cell lines by antisense oligodeoxynucleotides targeting p53 and p21 WAF1/CIP1. Cancer Gene Ther. 10:926–934. 2003. View Article : Google Scholar
24	Fernet M, Mégnin-Chanet F, Hall J and Favaudon V: Control of the G2/M checkpoints after exposure to low doses of ionising radiation: implications for hyper-radiosensitivity. DNA Repair (Amst). 9:48–57. 2010. View Article : Google Scholar
25	Zimmermann M, Arachchige-Don AS, Donaldson MS, Dallapiazza RF, Cowan CE and Horne MC: Elevated cyclin G2 expression intersects with DNA damage checkpoint signaling and is required for a potent G2/M checkpoint arrest response to doxorubicin. J Biol Chem. 287:22838–22853. 2012. View Article : Google Scholar : PubMed/NCBI
26	Fridman JS and Lowe SW: Control of apoptosis by p53. Oncogene. 22:9030–9040. 2003. View Article : Google Scholar : PubMed/NCBI
27	Zhang W, Gao R, Yu Y, Guo K, Liu Y and Yang A: Radioactive iodine-131 induces human thyrocyte cell line HTori 3 cell apoptosis and G2/M arrest in a p53-independent pathway. J Nucl Med Meeting Abstracts. 55:1422014.