Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1

Hirotada Tajiri, Takehito Uruno, Takahiro Shirai, Daisuke Takaya, Shigeki Matsunaga, Daiki Setoyama, Mayuki Watanabe, Mutsuko Kukimoto-Niino, Kounosuke Oisaki, Miho Ushijima, Fumiyuki Sanematsu, Teruki Honma, Takaho Terada, Eiji Oki, Senji Shirasawa, Yoshihiko Maehara, Dongchon Kang, Jean François Côté, Shigeyuki Yokoyama, Motomu KanaiYoshinori Fukui

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)969-980
Number of pages12
JournalCell Reports
Volume19
Issue number5
DOIs
Publication statusPublished - May 2 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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