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Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma
Cisplatin is one of the most effective chemotherapeutic agents commonly used for several malignancies including oral squamous cell carcinoma (OSCC). Although cisplatin resistance is a major obstacle to effective treatment and is associated with poor prognosis of OSCC patients, the molecular mechanis...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829433/ https://www.ncbi.nlm.nih.gov/pubmed/31635163 http://dx.doi.org/10.3390/ijms20205194 |
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author | Suenaga, Naoki Kuramitsu, Mimi Komure, Kanae Kanemaru, Ayumi Takano, Kanako Ozeki, Kazuya Nishimura, Yuka Yoshida, Ryoji Nakayama, Hideki Shinriki, Satoru Saito, Hideyuki Jono, Hirofumi |
author_facet | Suenaga, Naoki Kuramitsu, Mimi Komure, Kanae Kanemaru, Ayumi Takano, Kanako Ozeki, Kazuya Nishimura, Yuka Yoshida, Ryoji Nakayama, Hideki Shinriki, Satoru Saito, Hideyuki Jono, Hirofumi |
author_sort | Suenaga, Naoki |
collection | PubMed |
description | Cisplatin is one of the most effective chemotherapeutic agents commonly used for several malignancies including oral squamous cell carcinoma (OSCC). Although cisplatin resistance is a major obstacle to effective treatment and is associated with poor prognosis of OSCC patients, the molecular mechanisms by which it develops are largely unknown. Cylindromatosis (CYLD), a deubiquitinating enzyme, acts as a tumor suppressor in several malignancies. Our previous studies have shown that loss of CYLD expression in OSCC tissues is significantly associated with poor prognosis of OSCC patients. Here, we focused on CYLD expression in OSCC cells and determined whether loss of CYLD expression is involved in cisplatin resistance in OSCC and elucidated its molecular mechanism. In this study, to assess the effect of CYLD down-regulation on cisplatin resistance in human OSCC cell lines (SAS), we knocked-down the CYLD expression by using CYLD-specific siRNA. In cisplatin treatment, cell survival rates in CYLD knockdown SAS cells were significantly increased, indicating that CYLD down-regulation caused cisplatin resistance to SAS cells. Our results suggested that cisplatin resistance caused by CYLD down-regulation was associated with the mechanism through which both the reduction of intracellular cisplatin accumulation and the suppression of cisplatin-induced apoptosis via the NF-κB hyperactivation. Moreover, the combination of cisplatin and bortezomib treatment exhibited significant anti-tumor effects on cisplatin resistance caused by CYLD down-regulation in SAS cells. These findings suggest the possibility that loss of CYLD expression may cause cisplatin resistance in OSCC patients through NF-κB hyperactivation and may be associated with poor prognosis in OSCC patients. |
format | Online Article Text |
id | pubmed-6829433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68294332019-11-18 Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma Suenaga, Naoki Kuramitsu, Mimi Komure, Kanae Kanemaru, Ayumi Takano, Kanako Ozeki, Kazuya Nishimura, Yuka Yoshida, Ryoji Nakayama, Hideki Shinriki, Satoru Saito, Hideyuki Jono, Hirofumi Int J Mol Sci Article Cisplatin is one of the most effective chemotherapeutic agents commonly used for several malignancies including oral squamous cell carcinoma (OSCC). Although cisplatin resistance is a major obstacle to effective treatment and is associated with poor prognosis of OSCC patients, the molecular mechanisms by which it develops are largely unknown. Cylindromatosis (CYLD), a deubiquitinating enzyme, acts as a tumor suppressor in several malignancies. Our previous studies have shown that loss of CYLD expression in OSCC tissues is significantly associated with poor prognosis of OSCC patients. Here, we focused on CYLD expression in OSCC cells and determined whether loss of CYLD expression is involved in cisplatin resistance in OSCC and elucidated its molecular mechanism. In this study, to assess the effect of CYLD down-regulation on cisplatin resistance in human OSCC cell lines (SAS), we knocked-down the CYLD expression by using CYLD-specific siRNA. In cisplatin treatment, cell survival rates in CYLD knockdown SAS cells were significantly increased, indicating that CYLD down-regulation caused cisplatin resistance to SAS cells. Our results suggested that cisplatin resistance caused by CYLD down-regulation was associated with the mechanism through which both the reduction of intracellular cisplatin accumulation and the suppression of cisplatin-induced apoptosis via the NF-κB hyperactivation. Moreover, the combination of cisplatin and bortezomib treatment exhibited significant anti-tumor effects on cisplatin resistance caused by CYLD down-regulation in SAS cells. These findings suggest the possibility that loss of CYLD expression may cause cisplatin resistance in OSCC patients through NF-κB hyperactivation and may be associated with poor prognosis in OSCC patients. MDPI 2019-10-20 /pmc/articles/PMC6829433/ /pubmed/31635163 http://dx.doi.org/10.3390/ijms20205194 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Suenaga, Naoki Kuramitsu, Mimi Komure, Kanae Kanemaru, Ayumi Takano, Kanako Ozeki, Kazuya Nishimura, Yuka Yoshida, Ryoji Nakayama, Hideki Shinriki, Satoru Saito, Hideyuki Jono, Hirofumi Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma |
title | Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma |
title_full | Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma |
title_fullStr | Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma |
title_full_unstemmed | Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma |
title_short | Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma |
title_sort | loss of tumor suppressor cyld expression triggers cisplatin resistance in oral squamous cell carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829433/ https://www.ncbi.nlm.nih.gov/pubmed/31635163 http://dx.doi.org/10.3390/ijms20205194 |
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