title: Inhibition of β-catenin and STAT3 with a curcumin analog suppresses gastric carcinogenesis in vivo.
abstract: BACKGROUND
  Potent chemotherapy for advanced gastric cancer has not been completely established. Many molecularly targeted therapies are under investigation, but their therapeutic outcomes are not promising because they do not target specific and/or critical targets of gastric carcinogenesis. Although the molecular basis of gastric carcinogenesis remains poorly understood, nuclear localization of β-catenin was observed in approximately 50 % of gastric cancer specimens. Recent studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) contributes to gastric carcinogenesis in a mouse model. A newly synthesized curcumin analog has inhibitory potential against β-catenin and STAT3.
  
  
  METHODS
  Using a transgenic mouse model of gastric cancer in which β-catenin, cyclooxygenase 2, and microsomal prostaglandin E synthase 1 activation is induced, we examined a curcumin analog with the most enhanced potential for treating gastric cancer through oral administration. Inhibition of these targets was demonstrated using microarray and immunohistochemical analyses.
  
  
  RESULTS
  The curcumin analog GO-Y031 decreased the incidence of gastric carcinogenesis to 54.5 % of that of the control (50.0 % vs 91.7 %, p = 0.043), and tumor size was reduced to 51.6 % of that of the control (1.6 mm vs 3.1 mm, p = 0.03). β-Catenin and STAT3 levels were suppressed to 26.2 % (p = 0.00023) and 44.8 % (p = 0.025), respectively, of those of the control. Moreover, macrophage infiltration was suppressed with GO-Y031.
  
  
  CONCLUSIONS
  β-Catenin and STAT3 can be pharmacologically inhibited in vivo with a curcumin analog, which effectively inhibits β-catenin and STAT3.
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Akita University, Hondo 1-1-1, Akita, 010-8543, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Akita University, Hondo 1-1-1, Akita, 010-8543, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamakoshi
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hosoi
authors.affiliation: Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Iwabuchi
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Akita University, Hondo 1-1-1, Akita, 010-8543, Japan. hiroyuki@med.akita-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shibata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001555:Benzene Derivatives; D063646:Carcinogenesis / Q000187:drug effects*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007659:Ketones; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C541015:1,5-bis(3,5-bis(methoxymethoxy)phenyl)penta-1,4-dien-3-one; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; C495267:CTNNB1 protein, mouse; D007659:Ketones; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051176:beta Catenin; D003474:Curcumin
keywords: Analog; Curcumin; Gastric cancer; Signal transducer and activator of transcription 3; β-Catenin