Cargando…

PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Shuiping, Lin, Haoming, Wang, Da, Li, Qiang, Luo, Hong, Li, Guoxiong, Chen, Xiaohui, Li, Yongqiang, Chen, Peng, Zhai, Bingtao, Wang, Wengang, Zhang, Ruonan, Chen, Bi, Zhang, Mingming, Han, Xuemeng, Li, Qiujie, Chen, Liuxi, Liu, Ying, Chen, Xiaying, Li, Guohua, Xiang, Yu, Duan, Ting, Feng, Jiao, Lou, Jianshu, Huang, Xingxing, Zhang, Qin, Pan, Ting, Yan, Lili, Jin, Ting, Zhang, Wenzheng, Zhuo, Lvjia, Sun, Yitian, Xie, Tian, Sui, Xinbing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882894/
https://www.ncbi.nlm.nih.gov/pubmed/31815010
http://dx.doi.org/10.1038/s41392-019-0087-0
_version_ 1783474262279979008
author Liu, Shuiping
Lin, Haoming
Wang, Da
Li, Qiang
Luo, Hong
Li, Guoxiong
Chen, Xiaohui
Li, Yongqiang
Chen, Peng
Zhai, Bingtao
Wang, Wengang
Zhang, Ruonan
Chen, Bi
Zhang, Mingming
Han, Xuemeng
Li, Qiujie
Chen, Liuxi
Liu, Ying
Chen, Xiaying
Li, Guohua
Xiang, Yu
Duan, Ting
Feng, Jiao
Lou, Jianshu
Huang, Xingxing
Zhang, Qin
Pan, Ting
Yan, Lili
Jin, Ting
Zhang, Wenzheng
Zhuo, Lvjia
Sun, Yitian
Xie, Tian
Sui, Xinbing
author_facet Liu, Shuiping
Lin, Haoming
Wang, Da
Li, Qiang
Luo, Hong
Li, Guoxiong
Chen, Xiaohui
Li, Yongqiang
Chen, Peng
Zhai, Bingtao
Wang, Wengang
Zhang, Ruonan
Chen, Bi
Zhang, Mingming
Han, Xuemeng
Li, Qiujie
Chen, Liuxi
Liu, Ying
Chen, Xiaying
Li, Guohua
Xiang, Yu
Duan, Ting
Feng, Jiao
Lou, Jianshu
Huang, Xingxing
Zhang, Qin
Pan, Ting
Yan, Lili
Jin, Ting
Zhang, Wenzheng
Zhuo, Lvjia
Sun, Yitian
Xie, Tian
Sui, Xinbing
author_sort Liu, Shuiping
collection PubMed
description 5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.
format Online
Article
Text
id pubmed-6882894
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-68828942019-12-06 PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death Liu, Shuiping Lin, Haoming Wang, Da Li, Qiang Luo, Hong Li, Guoxiong Chen, Xiaohui Li, Yongqiang Chen, Peng Zhai, Bingtao Wang, Wengang Zhang, Ruonan Chen, Bi Zhang, Mingming Han, Xuemeng Li, Qiujie Chen, Liuxi Liu, Ying Chen, Xiaying Li, Guohua Xiang, Yu Duan, Ting Feng, Jiao Lou, Jianshu Huang, Xingxing Zhang, Qin Pan, Ting Yan, Lili Jin, Ting Zhang, Wenzheng Zhuo, Lvjia Sun, Yitian Xie, Tian Sui, Xinbing Signal Transduct Target Ther Article 5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients. Nature Publishing Group UK 2019-11-29 /pmc/articles/PMC6882894/ /pubmed/31815010 http://dx.doi.org/10.1038/s41392-019-0087-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Liu, Shuiping
Lin, Haoming
Wang, Da
Li, Qiang
Luo, Hong
Li, Guoxiong
Chen, Xiaohui
Li, Yongqiang
Chen, Peng
Zhai, Bingtao
Wang, Wengang
Zhang, Ruonan
Chen, Bi
Zhang, Mingming
Han, Xuemeng
Li, Qiujie
Chen, Liuxi
Liu, Ying
Chen, Xiaying
Li, Guohua
Xiang, Yu
Duan, Ting
Feng, Jiao
Lou, Jianshu
Huang, Xingxing
Zhang, Qin
Pan, Ting
Yan, Lili
Jin, Ting
Zhang, Wenzheng
Zhuo, Lvjia
Sun, Yitian
Xie, Tian
Sui, Xinbing
PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death
title PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death
title_full PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death
title_fullStr PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death
title_full_unstemmed PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death
title_short PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death
title_sort pcdh17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882894/
https://www.ncbi.nlm.nih.gov/pubmed/31815010
http://dx.doi.org/10.1038/s41392-019-0087-0
work_keys_str_mv AT liushuiping pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT linhaoming pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT wangda pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT liqiang pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT luohong pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT liguoxiong pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT chenxiaohui pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT liyongqiang pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT chenpeng pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT zhaibingtao pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT wangwengang pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT zhangruonan pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT chenbi pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT zhangmingming pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT hanxuemeng pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT liqiujie pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT chenliuxi pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT liuying pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT chenxiaying pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT liguohua pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT xiangyu pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT duanting pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT fengjiao pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT loujianshu pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT huangxingxing pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT zhangqin pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT panting pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT yanlili pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT jinting pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT zhangwenzheng pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT zhuolvjia pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT sunyitian pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT xietian pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath
AT suixinbing pcdh17increasesthesensitivityofcolorectalcancerto5fluorouraciltreatmentbyinducingapoptosisandautophagiccelldeath