mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat.
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.
Department of Emergency General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China. Electronic address: pengxinggang26@sina.com.
Xingang
X
Peng
Department of Infectious Disease, Linyi People's Hospital, Linyi, China. Electronic address: zhangdonghuiyx@sina.com.
Donghui
D
Zhang
Department of Nursing, Tengzhou Central People's Hospital, Tengzhou, China. Electronic address: lizhenglingzz@sina.com.
Zhengling
Z
Li
Department of Infectious Disease, Linyi People's Hospital, Linyi, China. Electronic address: fumeilidrlinyi@tom.com.
Meili
M
Fu
Department of Nursing, Linyi People's Hospital, Linyi, China. Electronic address: liuhaiyanlinyi5@sina.com.
Haiyan
H
Liu
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D004357:Drug Synergism; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D011743:Pyrimidines; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D001549:Benzamides; D006877:Hydroxamic Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009025:Morpholines; D011743:Pyrimidines; D013449:Sulfonamides; C585537:vistusertib; C550599:resminostat; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
Chemo-sensitization; HDACs; Hepatocellular carcinoma; Mitochondrial apoptosis pathway; Resminostat; mTOR