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

• Published in: Biochemical pharmacology 2014-06, Vol.89 (3), p.340-348
• Main Authors: Takahashi-Yanaga, Fumi, Yoshihara, Tatsuya, Jingushi, Kentaro, Igawa, Kazuhiro, Tomooka, Katsuhiko, Watanabe, Yutaka, Morimoto, Sachio, Nakatsu, Yoshimichi, Tsuzuki, Teruhisa, Nakabeppu, Yusaku, Sasaguri, Toshiyuki
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - therapeutic use; Cyclin D1 - genetics; Cyclin D1 - metabolism; DIF-1; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; Egr-1; Gene Expression Regulation, Neoplastic - drug effects; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3β; Hexanones - therapeutic use; Mice; Mice, Knockout; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Oxidative Stress; Phosphorylation; TCF7L2; Transcription Factor 7-Like 2 Protein - genetics; Transcription Factor 7-Like 2 Protein - metabolism; Wnt/β-catenin signaling pathway
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2014.03.006

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 Ser9 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 Ser9, 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.