Oncotarget

Research Papers:

Telomerase antagonist imetelstat increases radiation sensitivity in esophageal squamous cell carcinoma

Xuping Wu, Jing Zhang, Sijun Yang, Zhihui Kuang, Guolei Tan, Gang Yang, Qichun Wei, Zhigang Guo _

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Oncotarget. 2017; 8:13600-13610. https://doi.org/10.18632/oncotarget.14618

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Abstract

Xuping Wu1,*, Jing Zhang2,*, Sijun Yang3 , Zhihui Kuang2, Guolei Tan1, Gang Yang1, Qichun Wei4, Zhigang Guo2

1The Second Hospital of Nanjing Affiliated to Medical School of Southeast University, Nanjing 210003, China

2Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China

3ABSL-3 Laboratory at The Center for Animal Experiment and State Key Lab of Virology, Wuhan University, Wuhan 430071, China

4Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 31009, China

*These authors contributed equally to this work and as the first author

Correspondence to:

Zhigang Guo, email: guozgang@gmail.com

Xuping Wu, email: xuping_wu@yahoo.com

Keywords: esophageal squamous cell carcinoma, telomerase, radiosensitization, apoptosis

Received: January 17, 2016     Accepted: January 03, 2017     Published: January 13, 2017

ABSTRACT

The morbidity and mortality of esophageal cancer is one of the highest around the world and the principal therapeutic method is radiation. Thus, searching for sensitizers with lower toxicity and higher efficiency to improve the efficacy of radiation therapy is critical essential. Our research group has previously reported that imetelstat, the thio-phosphoramidate oligonucleotide inhibitor of telomerase, can decrease cell proliferation and colony formation ability as well as increase DNA breaks induced by radiation in esophageal cancer cells. Further study in this project showed that imetelstat significantly sensitized esophageal cancer cells to radiation in vitro. Later study showed that imetelstat leads to increased cell apoptosis. We also measured the expression level of several DNA repair and apoptosis signaling proteins. pS345 CHK1, γ-H2AX, p53 and caspase3 expression were up-regulated in imetelstat treated cells, identifying these factors as molecular markers. Mouse in vivo model using imetelstat at clinically achievable concentrations and fractionated irradiation scheme yielded results demonstrating radiosensitization effect. Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation. Our study supported imetelstat increase radiation sensitivity of esophageal squamous cell carcinoma through inducing cell apoptosis and the specific inhibitor of telomerase might serve as a potential novel therapeutic tool for esophageal squamous cell carcinoma therapy.


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