Abstract：
: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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Tajiri H,Uruno T,Shirai T,Takaya D,Matsunaga S,Setoyama D,Watanabe M,Kukimoto-Niino M,Oisaki K,Ushijima M,Sanematsu F,Honma T,Terada T,Oki E,Shirasawa S,Maehara Y,Kang D,Côté JF,Yokoyama S,Kanai M,Fukui Ydoi
10.1016/j.celrep.2017.04.016subject
Has Abstractpub_date
2017-05-02 00:00:00pages
969-980issue
5issn
2211-1247pii
S2211-1247(17)30491-6journal_volume
19pub_type
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