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

Hirotada Tajiri1, Takehito Uruno2, Takahiro Shirai3

  • 1Division 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.

Cell Reports
|May 4, 2017
PubMed

Insights

Targeting DOCK1, a key protein in cancer cell invasion and nutrient uptake, with the inhibitor TBOPP shows promise. This approach suppressed cancer growth and metastasis in vivo, offering a potential new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Oncogenic Ras proteins are crucial in cancer initiation and progression.
  • Ras-mediated malignant phenotypes involve nutrient uptake and invasive migration, which depend on Rac-mediated actin cytoskeleton remodeling.

Purpose of the Study:

  • To investigate the role of Rac-specific guanine nucleotide exchange factors (GEFs) in Ras-driven cancer.
  • To identify and characterize a selective inhibitor of DOCK1 for potential cancer therapy.

Main Methods:

  • Genetic inactivation of DOCK1 in Ras-transformed cells.
  • Chemical library screening to identify DOCK1 inhibitors.
  • In vitro assays to assess invasion, macropinocytosis, and cell survival.
  • In vivo studies in mice to evaluate metastasis and tumor growth suppression.

Main Results:

  • Genetic inactivation of DOCK1 inhibited macropinocytosis-dependent nutrient uptake and invasion in Ras-transformed cells.
  • TBOPP, a selective DOCK1 inhibitor, was identified and demonstrated to dampen DOCK1-mediated invasion, macropinocytosis, and survival under glutamine deprivation.
  • TBOPP did not affect the function of related proteins DOCK2 and DOCK5.
  • TBOPP treatment suppressed cancer metastasis and growth in vivo.

Conclusions:

  • DOCK1 is essential for Ras-driven cancer cell invasion and nutrient uptake.
  • Selective pharmacological inhibition of DOCK1 using TBOPP represents a potential therapeutic strategy against cancer cell survival and invasion.
  • Targeting DOCK1 may offer a novel approach to suppress cancer metastasis and growth.
Keywords:
DOCK1Rascancer cell invasioncancer cell survivalmacropinocytosismetabolismsmall-molecule inhibitor

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