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Title: mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat

Abstract

Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients’ poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A), or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat. - Highlights: • AZD-2014 potentiates resminostat’s cytotoxicity against HCC cells. • AZD-2014 facilitates resminostat-induced HCC cell apoptosis. • AZD-2014 augments resminostat-induced mitochondrial apoptosis pathway activation. • mTOR shRNA or kinase-dead mutation significantly sensitizes HCCmore » cells to resminostat.« less

Authors:
 [1];  [2];  [3];  [2];  [4]
  1. Department of Emergency General Surgery, The Affiliated Hospital of Qingdao University, Qingdao (China)
  2. Department of Infectious Disease, Linyi People’s Hospital, Linyi (China)
  3. Department of Nursing, Tengzhou Central People’s Hospital, Tengzhou (China)
  4. Department of Nursing, Linyi People’s Hospital, Linyi (China)
Publication Date:
OSTI Identifier:
22606175
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 477; Journal Issue: 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CELL PROLIFERATION; CYCLOSPORINE; HEPATOMAS; HISTONES; INHIBITION; MITOCHONDRIA; MUTATIONS; PATIENTS; PERMEABILITY; TOXICITY

Citation Formats

Peng, Xingang, E-mail: pengxinggang26@sina.com, Zhang, Donghui, E-mail: zhangdonghuiyx@sina.com, Li, Zhengling, E-mail: lizhenglingzz@sina.com, Fu, Meili, E-mail: fumeilidrlinyi@tom.com, and Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com. mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.06.060.
Peng, Xingang, E-mail: pengxinggang26@sina.com, Zhang, Donghui, E-mail: zhangdonghuiyx@sina.com, Li, Zhengling, E-mail: lizhenglingzz@sina.com, Fu, Meili, E-mail: fumeilidrlinyi@tom.com, & Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com. mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat. United States. doi:10.1016/J.BBRC.2016.06.060.
Peng, Xingang, E-mail: pengxinggang26@sina.com, Zhang, Donghui, E-mail: zhangdonghuiyx@sina.com, Li, Zhengling, E-mail: lizhenglingzz@sina.com, Fu, Meili, E-mail: fumeilidrlinyi@tom.com, and Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com. Fri . "mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat". United States. doi:10.1016/J.BBRC.2016.06.060.
@article{osti_22606175,
title = {mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat},
author = {Peng, Xingang, E-mail: pengxinggang26@sina.com and Zhang, Donghui, E-mail: zhangdonghuiyx@sina.com and Li, Zhengling, E-mail: lizhenglingzz@sina.com and Fu, Meili, E-mail: fumeilidrlinyi@tom.com and Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com},
abstractNote = {Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients’ poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A), or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat. - Highlights: • AZD-2014 potentiates resminostat’s cytotoxicity against HCC cells. • AZD-2014 facilitates resminostat-induced HCC cell apoptosis. • AZD-2014 augments resminostat-induced mitochondrial apoptosis pathway activation. • mTOR shRNA or kinase-dead mutation significantly sensitizes HCC cells to resminostat.},
doi = {10.1016/J.BBRC.2016.06.060},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 477,
place = {United States},
year = {Fri Sep 02 00:00:00 EDT 2016},
month = {Fri Sep 02 00:00:00 EDT 2016}
}