期刊
CELL REPORTS
卷 19, 期 5, 页码 969-980出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.04.016
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资金
- Leading Advanced Projects for Medical Innovation (LEAP) from Japan Agency for Medical Research and Development (AMED)
- Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from AMED
- Japan Society for the Promotion of Science [25251015, 15K06987]
- Center for Clinical and Translational Research of Kyushu University
- Takeda Science Foundation
- Canadian Institute for Health Research [MOP-144425]
- Senior FRQS career award
- Grants-in-Aid for Scientific Research [15K06987, 25251015, 16H02497, 16K08627, 17H01550] Funding Source: KAKEN
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.
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