DIF-1 inhibits tumor growth in vivo reducing phosphorylation of GSK-3beta and expressions of cyclin D1 and TCF7L2 in cancer model mice.
DIF-1 inhibits tumor growth in vivo reducing phosphorylation of GSK-3beta and expressions of cyclin D1 and TCF7L2 in cancer model mice.
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DIF-1 抑制体内肿瘤生长，减少癌症模型小鼠中 GSK-3beta 的磷酸化以及细胞周期蛋白 D1 和 TCF7L2 的表达。
DOI：
10.1016/j.bcp.2014.03.006
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发表时间：
2014
影响因子：
5.8
通讯作者：
T.
中科院分区：
文献类型：
--
作者：
Takahashi-Yanaga;F.;Yoshihara;T.;Jingushi;K.;Igawa;K.;Tomooka;K.;Watanabe;Y.;Morimoto;S.;Nakatsu;Y.;Tsuzuki;T.;Nakabeppu;Y.;and Sasaguri;T.
我们报道了由盘基网柄藻（Dictyosteelociddiscoideum）合成的分化诱导因子-1（DIF-1）通过抑制Wnt/β-catenin信号通路抑制多种肿瘤细胞系的增殖。然而，DIF-1是否也抑制体内肿瘤生长仍有待研究。因此，在本研究中，我们使用三种癌症模型检查DIF-1的体内效应：氧化应激诱导的肠肿瘤的Mutyh缺陷小鼠和人结肠癌细胞系HCT-116和宫颈癌细胞系HeLa异种移植的裸鼠。在探索适当的给药途径时，我们发现口服给药的DIF-1通过消化道吸收，从而将其血药浓度提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GSK-3β Ser 9的磷酸化水平以及早期生长反应-1（Egr-1）、转录因子7样2（TCF 7 L2）和细胞周期蛋白D1的表达水平。DIF-1还抑制HCT-116和HeLa异种移植肿瘤的生长，同时降低GSK-3β Ser 9的磷酸化水平，尽管在HeLa异种移植肿瘤中没有统计学显著性。DIF-1还抑制HCT-116异种移植瘤中Egr-1、TCF 7 L2和cyclin D1的表达以及HeLa异种移植瘤中β-catenin、TCF 7 L2和cyclin D1的表达。这是首次报道DIF-1在体内抑制肿瘤生长，与其体外作用一致，表明该化合物可能具有作为新型抗肿瘤剂的潜力。
We reported that differentiation-inducing factor-1 (DIF-1), synthesized byDictyostelium discoideum, inhibited proliferation of various tumor cell linesin vitroby suppressing the Wnt/β-catenin signaling pathway. However, it remained unexplored whether DIF-1 also inhibits tumor growthin vivo. In the present study, therefore, we examinedin-vivoeffects 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 inMutyh-deficient mice, reducing the phosphorylation level of GSK-3β Ser9and 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 growthin vivo, consistent with itsin-vitroaction, suggesting that this compound may have potential as a novel anti-tumor agent.