DIF-1 inhibits tumor growth in vivo reducing phosphorylation of GSK-3β and expressions of cyclin D1 and TCF7L2 in cancer model mice

Fumi Takahashi, Tatsuya Yoshihara, Kentaro Jingushi, Kazunobu Igawa, Katsuhiko Tomooka, Yutaka Watanabe, Sachio Morimoto, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Yusaku Nakabeppu, Toshiyuki Sasaguri

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)340-348
Number of pages9
JournalBiochemical Pharmacology
Volume89
Issue number3
DOIs
Publication statusPublished - Jun 1 2014

Fingerprint

T Cell Transcription Factor 1
Glycogen Synthase Kinase 3
Phosphorylation
Cyclin D1
Tumors
Growth
Neoplasms
Heterografts
Catenins
Cells
1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone
Cell Line
Wnt Signaling Pathway
Dictyostelium
Oxidative stress
Cell proliferation
Tumor Cell Line
Nude Mice
Uterine Cervical Neoplasms
Colonic Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

DIF-1 inhibits tumor growth in vivo reducing phosphorylation of GSK-3β and expressions of cyclin D1 and TCF7L2 in cancer model mice. / Takahashi, Fumi; Yoshihara, Tatsuya; Jingushi, Kentaro; Igawa, Kazunobu; Tomooka, Katsuhiko; Watanabe, Yutaka; Morimoto, Sachio; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Nakabeppu, Yusaku; Sasaguri, Toshiyuki.

In: Biochemical Pharmacology, Vol. 89, No. 3, 01.06.2014, p. 340-348.

Research output: Contribution to journalArticle

@article{21cda889fdd3458db34354c33c96cbd6,
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.",
author = "Fumi Takahashi and Tatsuya Yoshihara and Kentaro Jingushi and Kazunobu Igawa and Katsuhiko Tomooka and Yutaka Watanabe and Sachio Morimoto and Yoshimichi Nakatsu and Teruhisa Tsuzuki and Yusaku Nakabeppu and Toshiyuki Sasaguri",
year = "2014",
month = "6",
day = "1",
doi = "10.1016/j.bcp.2014.03.006",
language = "English",
volume = "89",
pages = "340--348",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - DIF-1 inhibits tumor growth in vivo reducing phosphorylation of GSK-3β and expressions of cyclin D1 and TCF7L2 in cancer model mice

AU - Takahashi, Fumi

AU - Yoshihara, Tatsuya

AU - Jingushi, Kentaro

AU - Igawa, Kazunobu

AU - Tomooka, Katsuhiko

AU - Watanabe, Yutaka

AU - Morimoto, Sachio

AU - Nakatsu, Yoshimichi

AU - Tsuzuki, Teruhisa

AU - Nakabeppu, Yusaku

AU - Sasaguri, Toshiyuki

PY - 2014/6/1

Y1 - 2014/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84899939959&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899939959&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2014.03.006

DO - 10.1016/j.bcp.2014.03.006

M3 - Article

VL - 89

SP - 340

EP - 348

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 3

ER -