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

Naoya Kubokura, Fumi Takahashi-Yanaga, Masaki Arioka, Tatsuya Yoshihara, Kazunobu Igawa, Katsuhiko Tomooka, Sachio Morimoto, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Yusaku Nakabeppu, Takayuki Matsumoto, Takanari Kitazono, Toshiyuki Sasaguri

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)446-455
Number of pages10
JournalJournal of Pharmacological Sciences
Volume127
Issue number4
DOIs
Publication statusPublished - Jan 1 2015

Fingerprint

Growth
Neoplasms
Intestinal Neoplasms
Catenins
Dictyostelium
Cyclin D1
1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone
In Vitro Techniques
Cell Proliferation
TCF Transcription Factors
Glycogen Synthase Kinase 3
Cell Cycle Resting Phase
Wnt Signaling Pathway
G1 Phase
Colonic Neoplasms
Oral Administration
Signal Transduction
Cell Cycle
Oxidative Stress
Transcription Factors

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo. / Kubokura, Naoya; Takahashi-Yanaga, Fumi; Arioka, Masaki; Yoshihara, Tatsuya; Igawa, Kazunobu; Tomooka, Katsuhiko; Morimoto, Sachio; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Nakabeppu, Yusaku; Matsumoto, Takayuki; Kitazono, Takanari; Sasaguri, Toshiyuki.

In: Journal of Pharmacological Sciences, Vol. 127, No. 4, 01.01.2015, p. 446-455.

Research output: Contribution to journalArticle

@article{c666604395144f15b59c168f749ca3d0,
title = "Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo",
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.",
author = "Naoya Kubokura and Fumi Takahashi-Yanaga and Masaki Arioka and Tatsuya Yoshihara and Kazunobu Igawa and Katsuhiko Tomooka and Sachio Morimoto and Yoshimichi Nakatsu and Teruhisa Tsuzuki and Yusaku Nakabeppu and Takayuki Matsumoto and Takanari Kitazono and Toshiyuki Sasaguri",
year = "2015",
month = "1",
day = "1",
doi = "10.1016/j.jphs.2015.03.005",
language = "English",
volume = "127",
pages = "446--455",
journal = "Journal of Pharmacological Sciences",
issn = "1347-8613",
publisher = "Japanese Pharmacological Society",
number = "4",

}

TY - JOUR

T1 - Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo

AU - Kubokura, Naoya

AU - Takahashi-Yanaga, Fumi

AU - Arioka, Masaki

AU - Yoshihara, Tatsuya

AU - Igawa, Kazunobu

AU - Tomooka, Katsuhiko

AU - Morimoto, Sachio

AU - Nakatsu, Yoshimichi

AU - Tsuzuki, Teruhisa

AU - Nakabeppu, Yusaku

AU - Matsumoto, Takayuki

AU - Kitazono, Takanari

AU - Sasaguri, Toshiyuki

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84938514386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938514386&partnerID=8YFLogxK

U2 - 10.1016/j.jphs.2015.03.005

DO - 10.1016/j.jphs.2015.03.005

M3 - Article

C2 - 25913757

AN - SCOPUS:84938514386

VL - 127

SP - 446

EP - 455

JO - Journal of Pharmacological Sciences

JF - Journal of Pharmacological Sciences

SN - 1347-8613

IS - 4

ER -