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  3. 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

  • Cell Rep. 2017 May 2;19(5):969-980. doi: 10.1016/j.celrep.2017.04.016.
Hirotada Tajiri 1,  Takehito Uruno 2,  Takahiro Shirai 3,  Daisuke Takaya 4,  Shigeki Matsunaga 5,  Daiki Setoyama 6,  Mayuki Watanabe 2,  Mutsuko Kukimoto-Niino 4,  Kounosuke Oisaki 3,  Miho Ushijima 7,  Fumiyuki Sanematsu 2,  Teruki Honma 4,  Takaho Terada 8,  Eiji Oki 9,  Senji Shirasawa 10,  Yoshihiko Maehara 9,  Dongchon Kang 6,  Jean-François Côté 11,  Shigeyuki Yokoyama 8,  Motomu Kanai 3,  Yoshinori Fukui 12
Affiliations

Affiliations

  • 1 Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • 2 Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan.
  • 3 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
  • 4 RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan.
  • 5 Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
  • 6 Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • 7 Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
  • 8 RIKEN Structural Biology Laboratory, Yokohama 230-0045, Japan.
  • 9 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • 10 Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
  • 11 Institut de Recherches Cliniques de Montréal (Université de Montréal), Montréal, QC H2W 1R7, Canada.
  • 12 Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: fukui@bioreg.kyushu-u.ac.jp.
PMID: 28467910 DOI: 10.1016/j.celrep.2017.04.016
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.

Keywords

DOCK1; Ras; cancer cell invasion; cancer cell survival; macropinocytosis; metabolism; small-molecule inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124711
    99.96%, DOCK1抑制剂
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