Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo
Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo
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DOI：
10.1016/j.jphs.2015.03.005
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发表时间：
2015-04-01
影响因子：
3.5
通讯作者：
Sasaguri, Toshiyuki
中科院分区：
文献类型：
--
作者：
Kubokura, Naoya;Takahashi-Yanaga, Fumi;Sasaguri, Toshiyuki
Dictyostelium disideum产生的分化诱导因子-1 （DIF-1）通过抑制Wnt/ β -catenin信号转导通路，强烈抑制多种类型癌细胞的增殖。在本研究中，我们研究了分化诱导因子-3 （DIF-3）对人结肠癌细胞系HCT-116和DLD-1的影响，DIF-3是DIF-1的一种单氯化代谢物，也由盘状盘状芽孢杆菌产生。DIF-3通过在G(0)/G(1)期阻滞细胞周期，强烈抑制细胞增殖。DIF-3通过激活GSK-3 β促进细胞周期蛋白D1和c-Myc的降解，以时间和剂量依赖性的方式降低细胞周期蛋白D1和c-Myc的表达水平。此外，DIF-3抑制Wnt/ β -catenin信号通路中的关键转录因子t细胞因子7-like 2的表达，从而降低cyclin D1和c-Myc的mRNA水平。随后，我们检测了DIF-3在氧化应激诱导的肠道癌症小鼠中的体内作用。重复口服DIF-3显著减少癌症的数量和大小，其水平与DIF-1相当。这些数据表明，DIF-3在体外和体内均能抑制肠道癌细胞的增殖，其机制可能与DIF-1的作用相似，DIF-3可能是一种潜在的新型抗癌药物。(C) 2015年作者。由Elsevier B.V.代表日本药理学会制作和主办。这是一篇基于CC BY-NC-ND许可（http://creativecommons.org/licenses/by-nc-nd/4.0/）的开放获取文章。
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/beta-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 G(0)/G(1) phase. DIF-3 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via activation of GSK-3 beta 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/beta-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. (C) 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).