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 »
- Authors:
-
- Department of Emergency General Surgery, The Affiliated Hospital of Qingdao University, Qingdao (China)
- Department of Infectious Disease, Linyi People’s Hospital, Linyi (China)
- Department of Nursing, Tengzhou Central People’s Hospital, Tengzhou (China)
- Department of Nursing, Linyi People’s Hospital, Linyi (China)
- Publication Date:
- OSTI Identifier:
- 22606175
- Resource Type:
- Journal Article
- Journal Name:
- Biochemical and Biophysical Research Communications
- Additional Journal Information:
- 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); Journal ID: ISSN 0006-291X
- 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, Zhang, Donghui, Li, Zhengling, Fu, Meili, and Liu, Haiyan. 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, Zhang, Donghui, Li, Zhengling, Fu, Meili, & Liu, Haiyan. mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat. United States. https://doi.org/10.1016/J.BBRC.2016.06.060
Peng, Xingang, Zhang, Donghui, Li, Zhengling, Fu, Meili, and Liu, Haiyan. 2016.
"mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat". United States. https://doi.org/10.1016/J.BBRC.2016.06.060.
@article{osti_22606175,
title = {mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat},
author = {Peng, Xingang and Zhang, Donghui and Li, Zhengling and Fu, Meili and Liu, Haiyan},
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},
url = {https://www.osti.gov/biblio/22606175},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
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}
}