Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1
Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1
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DOI：
10.1016/j.celrep.2017.04.016
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发表时间：
2017-05-02
期刊：
影响因子：
8.8
通讯作者：
Fukui, Yoshinori
中科院分区：
文献类型：
--
作者：
Tajiri, Hirotada;Uruno, Takehito;Fukui, Yoshinori
致癌Ras在癌症发生中发挥着关键作用，但也通过刺激营养吸收和促进侵袭性迁移而导致恶性表型。因为后面这些细胞反应需要 Rac 介导的肌动蛋白细胞骨架重塑，我们假设参与 Rac 激活的分子可能是癌症治疗的有价值的靶点。我们报告说，Rac 特异性鸟嘌呤核苷酸交换因子 DOCK1 的基因失活会消除 Ras 转化细胞中巨胞饮依赖性的营养吸收和细胞侵袭。通过筛选化学库，我们确定了 1-(2-(3'-(三氟甲基)[ 1,1'-联苯]-4-基)-2-氧代乙基)-5-吡咯烷基磺酰基-2(1H)-吡啶酮 (TBOPP) 作为 DOCK1 的选择性抑制剂。 TBOPP 抑制 DOCK1 介导的侵袭、巨胞饮作用和谷氨酰胺剥夺条件下的存活，而不损害密切相关的 DOCK2 和 DOCK5 蛋白的生物学功能。此外，TBOPP 治疗可抑制小鼠体内的癌症转移和生长。我们的结果表明，选择性药理学抑制 DOCK1 可能是一种针对癌细胞存活和侵袭的治疗方法。
Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3'-(trifluoromethyl)[ 1,1'-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.