1. Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1.
- Author
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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, and Fukui Y
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental drug therapy, Pinocytosis drug effects, Pyridones therapeutic use, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, rac GTP-Binding Proteins genetics, rac GTP-Binding Proteins metabolism, ras Proteins metabolism, Antineoplastic Agents pharmacology, Cell Movement drug effects, Pyridones pharmacology, rac GTP-Binding Proteins adverse effects
- 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., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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