title: DIF-1 inhibits tumor growth in vivo reducing phosphorylation of GSK-3β and expressions of cyclin D1 and TCF7L2 in cancer model mice.
abstract: We reported that differentiation-inducing factor-1 (DIF-1), synthesized by Dictyostelium discoideum, inhibited proliferation of various tumor cell lines in vitro by suppressing the Wnt/β-catenin signaling pathway. However, it remained unexplored whether DIF-1 also inhibits tumor growth in vivo. In the present study, therefore, we examined in-vivo effects of DIF-1 using three cancer models: Mutyh-deficient mice with oxidative stress-induced intestinal tumors and nude mice xenografted with the human colon cancer cell line HCT-116 and cervical cancer cell line HeLa. In exploration for an appropriate route of administration, we found that orally administered DIF-1 was absorbed through the digestive tract to elevate its blood concentration to levels enough to suppress tumor cell proliferation. Repeated oral administration of DIF-1 markedly reduced the number and size of intestinal tumors that developed in Mutyh-deficient mice, reducing the phosphorylation level of GSK-3β Ser(9) and the expression levels of early growth response-1 (Egr-1), transcription factor 7-like 2 (TCF7L2) and cyclin D1. DIF-1 also inhibited the growth of HCT-116- and HeLa-xenograft tumors together with decreasing phosphorylation level of GSK-3β Ser(9), although it was not statistically significant in HeLa-xenograft tumors. DIF-1 also suppressed the expressions of Egr-1, TCF7L2 and cyclin D1 in HCT-116-xenograft tumors and those of β-catenin, TCF7L2 and cyclin D1 in HeLa-xenograft tumors. This is the first report to show that DIF-1 inhibits tumor growth in vivo, consistent with its in-vitro action, suggesting that this compound may have potential as a novel anti-tumor agent.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: yanaga@cliphrarm.med.kyushu-u.ac.jp.
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshihara
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Jingushi
authors.affiliation: Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Igawa
authors.affiliation: Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tomooka
authors.affiliation: Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Tsuzuki
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: sasaguri@cliphrarm.med.kyushu-u.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006588:Hexanones / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006588:Hexanones; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; C053433:1-((3,5-dichloro)-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; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase
keywords: DIF-1; Egr-1; GSK-3β; TCF7L2; Wnt/β-catenin signaling pathway