Research Paper Volume 11, Issue 20 pp 8892—8910

TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway

Tian Yang 1, , Tianhe Huang 2, 3, , Dongdong Zhang 4, , Miao Wang 1, , Balu Wu 4, , Yufeng Shang 4, , Safat Sattar 1, , Lu Ding 4, , Yin Liu 1, , Hongqiang Jiang 4, , Yuxing Liang 4, , Fuling Zhou 4, , Yongchang Wei 1, ,

  • 1 Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
  • 2 Department of Clinical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
  • 3 Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
  • 4 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

received: July 3, 2019 ; accepted: September 22, 2019 ; published: October 19, 2019 ;

https://doi.org/10.18632/aging.102329
How to Cite

Copyright © 2019 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Radiotherapy is used to treat gastric cancer (GC); however, radioresistance challenges the clinical outcomes of GC, and the mechanisms of radioresistance in GC remain poorly understood. Here, we report that the TGF-β receptor inhibitor, LY2109761 (LY), is a potential radiosensitizer both in vitro and in vivo. As per the Cancer Genome Atlas database, TGF-β overexpression is significantly related to poor overall survival in GC patients. We demonstrated that the TGF-β/SMAD4 signaling pathway was activated in both radioresistant GC cells and radioresistant GC patients. As a TGF-β receptor inhibitor, LY can enhance the activities of irradiation by inhibiting cell proliferation, decreasing clonogenicity and increasing apoptosis. Moreover, LY attenuated the radiation-induced migration and invasion, epithelial-mesenchymal transition (EMT), inflammatory factor activation, immunosuppression, and cancer stem cell characteristics of GC cells, thus leading to radiosensitization of the GC cells. We confirmed that LY reduced tumor growth, inhibited TGF-β/SMAD4 pathway activation and reversed irradiation-induced EMT in a tumor xenograft model. Our findings indicate that the novel TGF-β receptor inhibitor, LY, increases GC radiosensitivity by directly regulating the TGF-β/SMAD4 signaling pathway. These findings provide new insight for radiotherapy in GC patients.

Abbreviations

TGF-β: Transforming growth factor-β; GC: gastric cancer; LY: LY2109761; IHC: immune- histochemistry; OS: overall survival; EMT: epithelial-mesenchymal transition; CSC: cancer stem cells; IR: ionizing radiation; TβR: TGF-β type receptor; SMAD: Drosophila mothers against decapentaplegic protein; PE: plating efficiency; SF: survival fraction; ALDH1: aldehydedehydrogenase 1; FACS: fluorescence-activated cell sorting; ROS: reactive oxygen species.