title: Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-κB Activation.
abstract: Metallothionein 2A (MT2A) and nuclear factor-kappaB (NF-κB) are both involved in carcinogenesis and cancer chemosensitivity. We previously showed decreased expression of MT2A and IκB-α in human gastric cancer (GC) associated with poor prognosis of GC patients. The present study investigated the effect of diallyl trisulfide (DATS), a garlic-derived compound, and docetaxel (DOC) on regulation of MT2A in relation to NF-κB in GC cells.
  
  
  
  DATS attenuated NF-κB signaling in GC cells, resulting in G2/M cell cycle arrest and apoptosis, culminating in the inhibition of cell proliferation and tumorigenesis in nude mice. The anti-GC effect of DATS was attributable to its capacity to epigenetically upregulate MT2A, which in turn enhanced transcription of IκB-α to suppress NF-κB activation in GC cells. The combination of DATS with DOC exhibited a synergistic anti-GC activity accompanied by MT2A upregulation and NF-κB inactivation. Histopathologic analysis of GC specimens from patients showed a significant increase in MT2A expression following DOC treatment. GC patients with high MT2A expression in tumor specimens showed significantly improved response to chemotherapy and prolonged survival compared with those with low MT2A expression in tumors.
  
  
  
  We conclude that DATS exerts its anti-GC activity and enhances chemosensitivity of GC to DOC by epigenetic upregulation of MT2A to attenuate NF-κB signaling. Our findings delineate a mechanistic basis of MT2A/NF-κB signaling for DATS- and DOC-mediated anti-GC effects, suggesting that MT2A may be a chemosensitivity indicator in GC patients receiving DOC-based treatment and a promising target for more effective treatment of GC by combination of DATS and DOC. Antioxid. Redox Signal. 24, 839-854.
authors.affiliation: 1 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute , Beijing, P.R. China .
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Pan
authors.affiliation: 2 College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, 3 Shangyuancun, Haidian District, Beijing, P.R. China .|3 Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Shuye
authors.initials: S
authors.lastname: Lin
authors.affiliation: 1 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute , Beijing, P.R. China .
authors.forename: Rui
authors.initials: R
authors.lastname: Xing
authors.affiliation: 1 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute , Beijing, P.R. China .
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: 2 College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, 3 Shangyuancun, Haidian District, Beijing, P.R. China .
authors.forename: Bonan
authors.initials: B
authors.lastname: Lin
authors.affiliation: 1 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute , Beijing, P.R. China .
authors.forename: Jiantao
authors.initials: J
authors.lastname: Cui
authors.affiliation: 1 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute , Beijing, P.R. China .
authors.forename: Wenmei
authors.initials: W
authors.lastname: Li
authors.affiliation: 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology , Peking Cancer Hospital, Beijing, P.R. China .
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology , Peking Cancer Hospital, Beijing, P.R. China .
authors.forename: Lin
authors.initials: L
authors.lastname: Shen
authors.affiliation: 5 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China , Beijing, P.R. China .
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 6 Department of Gastroenterology and Hepatology, Chinese PLA General Hospital , Beijing, P.R. China .
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
authors.affiliation: 3 Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.affiliation: 2 College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, 3 Shangyuancun, Haidian District, Beijing, P.R. China .|3 Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: 1 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute , Beijing, P.R. China .
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D013440:Sulfides / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*; D015533:Transcriptional Activation; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000498:Allyl Compounds; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C491053:MT2A protein, human; D016328:NF-kappa B; D013440:Sulfides; D043823:Taxoids; C042577:diallyl trisulfide; D000077143:Docetaxel; D008668:Metallothionein