title: Inhibition of mTOR signalling potentiates the effects of trichostatin A in human gastric cancer cell lines by promoting histone acetylation.
abstract: Deregulation of the mammalian target of rapamycin pathway (mTOR pathway) is associated with human cancer. The relationship between mTOR pathway and histone acetylation is still unclear in gastric cancer (GC). Immunohistochemistry was used to examine the phosphorylation of mTOR and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in GC tissues. MKN45 and SGC7901 cells were treated with the mTOR inhibitor rapamycin (RAPA) alone or in combination with the phosphatidylinositol 3-kinase inhibitor LY294002 and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Small interfering RNA (siRNA) technology was also used to knockdown mTOR. Phosphorylated mTOR and phosphorylated 4E-BP1 were expressed in 71.1% and 68.4% of the human GC tissues tested, respectively; significantly higher than the levels in para-cancerous tissues (50% and 57.9%) and normal tissues (44.6% and 29%). RAPA markedly inhibited cell proliferation, induced G1 cell cycle arrest, and reduced phosphorylation of p70 S6 protein kinase (p70S6K) and 4E-BP1 in GC cells, particularly when used in combination with LY294002 or TSA. The mRNA expression of the tumour suppressor gene p21(WAF1) increased significantly in GC cells treated with both RAPA and TSA. Histone acetylation also increased after RAPA and TSA treatment or siRNA knockdown of mTOR. Our findings suggest that the mTOR pathway is activated in GC, and also that inhibition of mTOR enhances the ability of TSA to suppress cell proliferation and lead to cell cycle arrest via increasing histone acetylation and p21(WAF1) transcription in human MKN45 and SGC7901 GC cells.
authors.affiliation: Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health (Shanghai Jiao Tong University), 145 Middle Shandong Rd., Shanghai, 200001, China.
authors.forename: Dan-feng
authors.initials: DF
authors.lastname: Sun
authors.forename: Yan-jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Xiao-qing
authors.initials: XQ
authors.lastname: Tian
authors.forename: Ying-xuan
authors.initials: YX
authors.lastname: Chen
authors.forename: Jing-yuan
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C012589:trichostatin A; C546842:MTOR protein, human
keywords: deacetylase; epigenetic; gastric cancer; mammalian target of rapamycin; p21