title: Trichostatin A potentiates TRAIL-induced antitumor effects via inhibition of ERK/FOXM1 pathway in gastric cancer.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal apoptosis inducer and believed to have promise in cancer therapy, yet part of cancer cells exhibit resistance to TRAIL-mediated apoptosis. This necessitates the exploration of agents that resensitizes cancer cells to TRAIL. In our study, we found that Trichostatin A (TSA), an histone deacetylase (HDAC) inhibitor, augmented TRAIL-induced apoptosis in gastric cancer cells in a caspase-dependent manner. Besides, upregulation of DR5 and downregulation of anti-apoptotic proteins including XIAP, Mcl-1, Bcl-2 and Survivin also contributed to this synergism. Noticeably, TSA treatment inhibited Forkhead boxM1 (FOXM1), which expression level showed negative correlation with TRAIL sensitivity. Similarly, silencing of FOXM1 by small interfering RNA (siRNA) resensitized cancer cells to TRAIL and strengthened the TRAIL-augmenting effect of TSA. In addition, we demonstrated the depletion of FOXM1 was a consequence of the inactivation of ERK mediated by TSA. Collectively, it was first shown that TSA potentiated TRAIL sensitivity via ERK/FOXM1 pathway in gastric cancer cells. FOXM1 might serve as a biomarker for predicting sensitivity to TRAIL.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.|Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute Beijing, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute Beijing, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Fan
authors.affiliation: Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute Beijing, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.|The Tissue Bank, Peking University Cancer Hospital & Institute, Fu-Cheng Road, Beijing, China.
authors.forename: Lian-Hai
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Xing
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Cheng
authors.affiliation: The Tissue Bank, Peking University Cancer Hospital & Institute, Fu-Cheng Road, Beijing, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China. wenxz@bjmu.edu.cn.
authors.forename: Xian-Zi
authors.initials: XZ
authors.lastname: Wen
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China. jiafuji@outlook.com.|Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute Beijing, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China. jiafuji@outlook.com.
authors.forename: Jia-Fu
authors.initials: JF
authors.lastname: Ji
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C012589:trichostatin A
keywords: Combination therapy; ERK; FOXM1; Gastric cancer; TRAIL; Trichostatin A
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