Inhibition of survivin enhances radiosensitivity of esophageal cancer cells by switching radiation-induced senescence to apoptosis

Xianghe Liu; Yahui Zhao; Weina Zhang; Yang Gao; Miaomiao Huo; Mei Liu; Zefen Xiao; Shufang Liang; Ningzhi Xu; Hongxia Zhu

doi:10.2147/OTT.S166798

Inhibition of survivin enhances radiosensitivity of esophageal cancer cells by switching radiation-induced senescence to apoptosis

Onco Targets Ther. 2018 May 24:11:3087-3100. doi: 10.2147/OTT.S166798. eCollection 2018.

Authors

Xianghe Liu¹, Yahui Zhao¹, Weina Zhang¹, Yang Gao¹, Miaomiao Huo¹, Mei Liu¹, Zefen Xiao², Shufang Liang³, Ningzhi Xu^{1

3}, Hongxia Zhu¹

Affiliations

¹ Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.

Abstract

Purpose: Strategies to increase radiosensitivity are urgently needed. Combining radiosensitizing reagents with radiotherapy could improve the outcome of cancer treatment. Some preclinical studies showed that sepantronium bromide (YM155) could sensitize cancer cells to radiation by inhibiting the survivin protein. In this study, we try to investigate the function of YM155 on radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells.

Materials and methods: ESCC cell lines were treated with radiation and YM155, and the radiation efficacy was evaluated by cell counting kit-8 assay and clonogenic survival assay. Cell senescence was measured by senescence-associated β-galactosidase staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, fluorescein isothiocyanate-labeled Annexin V/propidium iodide assay, and poly ADP-ribose polymerase cleavage were used to detect apoptosis. KYSE150 xenografts model was used to test the efficacy of radiation combined with YM155.

Results: YM155 could inhibit the upregulation of survivin induced by radiation in all ESCC cell lines, but the efficacy of radiosensitization varied in different cell lines. Radiation-induced senescence in KYSE150 and KYSE410 cells, and the combination with YM155 inhibited senescence and promoted apoptosis of ESCC cells, thereby enhancing radiosensitivity. Combination with YM155 and radiation delayed the growth of KYSE150 xenografts in nude mice by switching radiation-induced senescence to apoptosis. When p21 was inhibited in KYSE150 cells, radiation did not induce senescence, and the radiosensitization of YM155 was also attenuated. In KYSE510 and KYSE180 cells, radiation did not induce senescence, and YM155 could not enhance the radiosensitivity.

Conclusion: Our results suggest a new mechanism that YM155 might sensitize ESCC cells to radiation by switching radiation-induced senescence to apoptosis. The major determinant of radiosensitization by YM155 might be the induction of senescence by radiation.

Keywords: YM155; esophageal squamous cell carcinoma; radiosensitivity; senescence; survivin.