Histone Deacetylase Inhibitors Inhibit the Proliferation of Gallbladder Carcinoma Cells by Suppressing AKT/mTOR Signaling.
Gallbladder carcinoma is an aggressive malignancy with high mortality mainly due to the limited potential for curative resection and its resistance to chemotherapeutic agents. Here, we show that the histone deacetylase inhibitors (HDACIs) trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA) reduce the proliferation and induce apoptosis of gallbladder carcinoma cells by suppressing the AKT/mammalian target of rapamycin (mTOR) signaling. Gallbladder carcinoma SGC-996 cells were treated with different concentrations of TSA and SAHA for different lengths of time. Cell proliferation and morphology were assessed with MTT assay and microscopy, respectively. Cell cycle distribution and cell apoptosis were analyzed with flow cytometry. Western blotting was used to detect the proteins related to apoptosis, cell cycle, and the AKT/mTOR signaling pathway. Our data showed that TSA and SAHA reduced SGC-996 cell viability and arrested cell cycle at the G1 phase in a dose- and time-dependent manner. TSA and SAHA promoted apoptosis of SGC-996 cells, down-regulated the expression of cyclin D1, c-Myc and Bmi1, and decreased the phosphorylation of AKT, mTOR p70S6K1, S6 and 4E-BP1. Additionally, the mTOR inhibitor rapamycin further reduced the cell viability of TSA- and SAHA-treated SGC-996 cells and the phosphorylation of mTOR, whereas the mTOR activator 1,2-dioctanoyl-sn-glycero-3-phosphate (C8-PA) exerted the opposite influence. Our results demonstrate that histone deacetylase inhibitors (HDACIs) suppress the proliferation of gallbladder carcinoma cell via inhibition of AKT/mTOR signaling. These findings offer a mechanistic rationale for the application of HDACIs in gallbladder carcinoma treatment.
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Peng
P
Zhang
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Zhiyong
Z
Guo
Department of Biostatistics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Ying
Y
Wu
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Ronglin
R
Hu
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Jun
J
Du
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Xiaoshun
X
He
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Xingyuan
X
Jiao
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Xiaofeng
X
Zhu
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077337:Vorinostat
D000970:Antineoplastic Agents; C069077:BMI1 protein, human; C530104:CCND1 protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; C012589:trichostatin A; D000077337:Vorinostat; D063150:Polycomb Repressive Complex 1; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus