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Title: Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma

Abstract

Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis. Methods and Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line. Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylatedmore » by the DNA demethylating agent 5-aza-2′-deoxycytidine. Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation.« less

Authors:
 [1];  [2];  [2];  [3];  [1];  [4];  [5];  [4]
  1. Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of)
  2. Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of)
  3. Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of)
  4. Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)
  5. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)
Publication Date:
OSTI Identifier:
22416539
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 88; Journal Issue: 5; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; APOPTOSIS; CARCINOMAS; DEOXYCYTIDINE; DNA; HEAD; METHYLATION; NECK; PATIENTS; POLYMERASE CHAIN REACTION; RADIOPROTECTIVE SUBSTANCES; RADIOTHERAPY; RECEPTORS; SURGERY

Citation Formats

Lee, Jong Cheol, Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Lee, Won Hyeok, Min, Young Joo, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Cha, Hee Jeong, Han, Myung Woul, Chang, Hyo Won, Kim, Sun-A, Choi, Seung-Ho, Kim, Seong Who, E-mail: swhokim@gmail.com, Kim, Sang Yoon, E-mail: sykim3715@gmail.com, and Biomedical Research Institute, Korea Institute of Science and Technology, Seoul. Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma. United States: N. p., 2014. Web. doi:10.1016/J.IJROBP.2013.12.016.
Lee, Jong Cheol, Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Lee, Won Hyeok, Min, Young Joo, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Cha, Hee Jeong, Han, Myung Woul, Chang, Hyo Won, Kim, Sun-A, Choi, Seung-Ho, Kim, Seong Who, E-mail: swhokim@gmail.com, Kim, Sang Yoon, E-mail: sykim3715@gmail.com, & Biomedical Research Institute, Korea Institute of Science and Technology, Seoul. Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma. United States. https://doi.org/10.1016/J.IJROBP.2013.12.016
Lee, Jong Cheol, Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Lee, Won Hyeok, Min, Young Joo, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Cha, Hee Jeong, Han, Myung Woul, Chang, Hyo Won, Kim, Sun-A, Choi, Seung-Ho, Kim, Seong Who, E-mail: swhokim@gmail.com, Kim, Sang Yoon, E-mail: sykim3715@gmail.com, and Biomedical Research Institute, Korea Institute of Science and Technology, Seoul. 2014. "Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma". United States. https://doi.org/10.1016/J.IJROBP.2013.12.016.
@article{osti_22416539,
title = {Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma},
author = {Lee, Jong Cheol and Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan and Lee, Won Hyeok and Min, Young Joo and Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan and Cha, Hee Jeong and Han, Myung Woul and Chang, Hyo Won and Kim, Sun-A and Choi, Seung-Ho and Kim, Seong Who, E-mail: swhokim@gmail.com and Kim, Sang Yoon, E-mail: sykim3715@gmail.com and Biomedical Research Institute, Korea Institute of Science and Technology, Seoul},
abstractNote = {Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis. Methods and Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line. Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylated by the DNA demethylating agent 5-aza-2′-deoxycytidine. Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation.},
doi = {10.1016/J.IJROBP.2013.12.016},
url = {https://www.osti.gov/biblio/22416539}, journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 5,
volume = 88,
place = {United States},
year = {Tue Apr 01 00:00:00 EDT 2014},
month = {Tue Apr 01 00:00:00 EDT 2014}
}