BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells
Abstract Aim JQ1, a BET bromodomain inhibitor, is a promising therapeutic approach for bladder cancer (BC). Our study aimed to determine whether autophagy is induced by JQ1 and its potential role toward proliferation in BC. Methods Cell proliferation was determined by methylthiazolyldiphenyl‐tetrazo...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Wiley
2019-08-01
|
Series: | Cancer Medicine |
Subjects: | |
Online Access: | https://doi.org/10.1002/cam4.2385 |
id |
doaj-aa27caa4427e429cb3cf99a57551ac28 |
---|---|
record_format |
Article |
spelling |
doaj-aa27caa4427e429cb3cf99a57551ac282020-11-25T00:40:20ZengWileyCancer Medicine2045-76342019-08-018104792480510.1002/cam4.2385BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cellsFeng Li0Chao Yang1Hai‐Bao Zhang2Jianbin Ma3Jing Jia4Xiaoshuang Tang5Jin Zeng6Tie Chong7Xinyang Wang8Dalin He9Peng Guo10Department of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an ChinaAbstract Aim JQ1, a BET bromodomain inhibitor, is a promising therapeutic approach for bladder cancer (BC). Our study aimed to determine whether autophagy is induced by JQ1 and its potential role toward proliferation in BC. Methods Cell proliferation was determined by methylthiazolyldiphenyl‐tetrazolium bromide (MTT) assay, cell counting assay, and colony formation assay. Autophagosomes and autolysosomes were observed by transmission electron microscopy and mRFP‐EGFP‐LC3 fluorescence assay. 3‐MA, BAFA1, NH4Cl, and siATG5 were used to inhibit autophagy. AMPK siRNA was used to knock down AMPK. T24 xenograft model in mice was chosen to perform in vivo studies. Autophagy markers LC‐3B and p62, p‐AMPKα, p‐ACC, p‐ULK1, p‐mTOR and p‐LKB1 were determined by western blot in vitro studies and by immunohistochemistry (IHC) in vivo specimens. Results We found that BC cell proliferation was suppressed by JQ1; moreover, JQ1 induced the accumulation of autophagosomes and autolysosomes, and autophagy flux, and the growth suppression capacity of JQ1 was attenuated by autophagy inhibitors. Furthermore, we found that JQ1 induced the phosphorylation of AMPKα, and AMPKα knockdown attenuated autophagy induction and anti‐proliferation effect induced by JQ1 in BC cells, indicating that autophagy induced by JQ1 is dependent on AMPKα. Through endogenous immunoprecipitation analysis, we found that JQ1 dramatically increased the interaction between LKB1 and AMPKα, which may lead to more AMPK activation. Proliferation inhibition, autophagy induction, and LKB1/AMPK activation capacities of JQ1 were further confirmed in vivo. Conclusions Taken together, our results demonstrate that autophagy is induced by JQ1 through activation of LKB1/AMPK pathway, and the autophagy induced by JQ1 positively contributes to the inhibition of BC cell proliferation. These findings provide a novel point of view to understand the mechanism of how targeting BET bromodomain suppress cancer cell growth and suggest that targeting BET bromodomain might be a potential approach to treat BC in the future.https://doi.org/10.1002/cam4.2385AMPKαautophagybladder cancerJQ1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Feng Li Chao Yang Hai‐Bao Zhang Jianbin Ma Jing Jia Xiaoshuang Tang Jin Zeng Tie Chong Xinyang Wang Dalin He Peng Guo |
spellingShingle |
Feng Li Chao Yang Hai‐Bao Zhang Jianbin Ma Jing Jia Xiaoshuang Tang Jin Zeng Tie Chong Xinyang Wang Dalin He Peng Guo BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells Cancer Medicine AMPKα autophagy bladder cancer JQ1 |
author_facet |
Feng Li Chao Yang Hai‐Bao Zhang Jianbin Ma Jing Jia Xiaoshuang Tang Jin Zeng Tie Chong Xinyang Wang Dalin He Peng Guo |
author_sort |
Feng Li |
title |
BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells |
title_short |
BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells |
title_full |
BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells |
title_fullStr |
BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells |
title_full_unstemmed |
BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells |
title_sort |
bet inhibitor jq1 suppresses cell proliferation via inducing autophagy and activating lkb1/ampk in bladder cancer cells |
publisher |
Wiley |
series |
Cancer Medicine |
issn |
2045-7634 |
publishDate |
2019-08-01 |
description |
Abstract Aim JQ1, a BET bromodomain inhibitor, is a promising therapeutic approach for bladder cancer (BC). Our study aimed to determine whether autophagy is induced by JQ1 and its potential role toward proliferation in BC. Methods Cell proliferation was determined by methylthiazolyldiphenyl‐tetrazolium bromide (MTT) assay, cell counting assay, and colony formation assay. Autophagosomes and autolysosomes were observed by transmission electron microscopy and mRFP‐EGFP‐LC3 fluorescence assay. 3‐MA, BAFA1, NH4Cl, and siATG5 were used to inhibit autophagy. AMPK siRNA was used to knock down AMPK. T24 xenograft model in mice was chosen to perform in vivo studies. Autophagy markers LC‐3B and p62, p‐AMPKα, p‐ACC, p‐ULK1, p‐mTOR and p‐LKB1 were determined by western blot in vitro studies and by immunohistochemistry (IHC) in vivo specimens. Results We found that BC cell proliferation was suppressed by JQ1; moreover, JQ1 induced the accumulation of autophagosomes and autolysosomes, and autophagy flux, and the growth suppression capacity of JQ1 was attenuated by autophagy inhibitors. Furthermore, we found that JQ1 induced the phosphorylation of AMPKα, and AMPKα knockdown attenuated autophagy induction and anti‐proliferation effect induced by JQ1 in BC cells, indicating that autophagy induced by JQ1 is dependent on AMPKα. Through endogenous immunoprecipitation analysis, we found that JQ1 dramatically increased the interaction between LKB1 and AMPKα, which may lead to more AMPK activation. Proliferation inhibition, autophagy induction, and LKB1/AMPK activation capacities of JQ1 were further confirmed in vivo. Conclusions Taken together, our results demonstrate that autophagy is induced by JQ1 through activation of LKB1/AMPK pathway, and the autophagy induced by JQ1 positively contributes to the inhibition of BC cell proliferation. These findings provide a novel point of view to understand the mechanism of how targeting BET bromodomain suppress cancer cell growth and suggest that targeting BET bromodomain might be a potential approach to treat BC in the future. |
topic |
AMPKα autophagy bladder cancer JQ1 |
url |
https://doi.org/10.1002/cam4.2385 |
work_keys_str_mv |
AT fengli betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT chaoyang betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT haibaozhang betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT jianbinma betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT jingjia betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT xiaoshuangtang betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT jinzeng betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT tiechong betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT xinyangwang betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT dalinhe betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells AT pengguo betinhibitorjq1suppressescellproliferationviainducingautophagyandactivatinglkb1ampkinbladdercancercells |
_version_ |
1725290806788489216 |