Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo.
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.
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.
Naoya
N
Kubokura
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.
Fumi
F
Takahashi-Yanaga
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Masaki
M
Arioka
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Tatsuya
T
Yoshihara
Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, 816-8580, Japan.
Kazunobu
K
Igawa
Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, 816-8580, Japan.
Katsuhiko
K
Tomooka
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Sachio
S
Morimoto
Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Yoshimichi
Y
Nakatsu
Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Teruhisa
T
Tsuzuki
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.
Yusaku
Y
Nakabeppu
Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, 020-0023, Japan.
Takayuki
T
Matsumoto
Department of Medicine and Clinical Science, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Takanari
T
Kitazono
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Toshiyuki
T
Sasaguri
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D006588:Hexanones / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008822:Mice, Transgenic; D018384:Oxidative Stress; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000502:physiology
D000970:Antineoplastic Agents; D006588:Hexanones; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; C053433:1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone; C055364:1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
DIF-3; TCF7L2; Wnt/β-catenin signaling pathway; c-Myc; cyclin D1