2. Academic Validation
  3. Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo

Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo

  • J Pharmacol Sci. 2015 Apr;127(4):446-55. doi: 10.1016/j.jphs.2015.03.005.
Naoya Kubokura 1,  Fumi Takahashi-Yanaga 2,  Masaki Arioka 3,  Tatsuya Yoshihara 3,  Kazunobu Igawa 4,  Katsuhiko Tomooka 4,  Sachio Morimoto 3,  Yoshimichi Nakatsu 5,  Teruhisa Tsuzuki 5,  Yusaku Nakabeppu 6,  Takayuki Matsumoto 7,  Takanari Kitazono 8,  Toshiyuki Sasaguri 3
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan; Department of Medicine and Clinical Science, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 2 Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan; Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Electronic address: yanaga@clipharm.med.kyushu-u.ac.jp.
  • 3 Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • 4 Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, 816-8580, Japan.
  • 5 Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • 6 Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.
  • 7 Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, 020-0023, Japan.
  • 8 Department of Medicine and Clinical Science, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
PMID: 25913757 DOI: 10.1016/j.jphs.2015.03.005
Abstract

Differentiation-inducing factor-1 (DIF-1) produced by Dictyostelium discoideum strongly inhibits the proliferation of various types of Cancer cells by suppression of the Wnt/β-catenin signal transduction pathway. In the present study, we examined the effect of differentiation-inducing factor-3 (DIF-3), a monochlorinated metabolite of DIF-1 that is also produced by D. discoideum, on human colon Cancer cell lines HCT-116 and DLD-1. DIF-3 strongly inhibited cell proliferation by arresting the cell cycle at the G0/G1 phase. DIF-3 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via activation of GSK-3β in a time and dose-dependent manner. In addition, DIF-3 suppressed the expression of T-cell factor 7-like 2, a key transcription factor in the Wnt/β-catenin signaling pathway, thereby reducing the mRNA levels of cyclin D1 and c-Myc. Subsequently, we examined the in vivo effects of DIF-3 in Mutyh(-/-) mice with oxidative stress-induced intestinal cancers. Repeated oral administration of DIF-3 markedly reduced the number and size of cancers at a level comparable to that of DIF-1. These data suggest that DIF-3 inhibits intestinal Cancer cell proliferation in vitro and in vivo, probably by mechanisms similar to those identified in DIF-1 actions, and that DIF-3 may be a potential novel anti-cancer agent.

Keywords

DIF-3; TCF7L2; Wnt/β-catenin signaling pathway; c-Myc; cyclin D1.

Figures
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  • HY-145669
    98.07%, Cyclin D1 Inhibitor