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
  • 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: [email protected].
  • 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.
Products