Takahashi-Yanaga Fumi, Yoshihara Tatsuya, Jingushi Kentaro, Igawa Kazuhiro, Tomooka Katsuhiko, Watanabe Yutaka, Morimoto Sachio, Nakatsu Yoshimichi, Tsuzuki Teruhisa, Nakabeppu Yusaku, Sasaguri Toshiyuki
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.
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Biochem Pharmacol. 2014 Jun 1;89(3):340-8. doi: 10.1016/j.bcp.2014.03.006. Epub 2014 Mar 23.
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.
我们曾报道，盘基网柄菌合成的分化诱导因子-1（DIF-1）通过抑制Wnt/β-连环蛋白信号通路，在体外抑制多种肿瘤细胞系的增殖。然而，DIF-1是否也能在体内抑制肿瘤生长仍未得到探索。因此，在本研究中，我们使用三种癌症模型来检测DIF-1的体内作用：具有氧化应激诱导肠道肿瘤的Mutyh缺陷小鼠，以及接种了人结肠癌细胞系HCT-116和宫颈癌细胞系HeLa的裸鼠。在探索合适的给药途径时，我们发现口服的DIF-1可通过消化道吸收，使血液浓度升高到足以抑制肿瘤细胞增殖的水平。重复口服DIF-1可显著减少Mutyh缺陷小鼠肠道肿瘤的数量和大小，降低糖原合成酶激酶-3β丝氨酸（9）位点的磷酸化水平以及早期生长反应-1（Egr-1）、转录因子7样2（TCF7L2）和细胞周期蛋白D1的表达水平。DIF-1还抑制了HCT-116和HeLa异种移植肿瘤的生长，同时降低了糖原合成酶激酶-3β丝氨酸（9）位点的磷酸化水平，尽管在HeLa异种移植肿瘤中这一作用无统计学意义。DIF-1还抑制了HCT-116异种移植肿瘤中Egr-1、TCF7L2和细胞周期蛋白D1的表达，以及HeLa异种移植肿瘤中β-连环蛋白、TCF7L2和细胞周期蛋白D1的表达。这是首份表明DIF-1在体内抑制肿瘤生长的报告，与其体外作用一致，提示该化合物可能具有作为新型抗肿瘤药物的潜力。
