Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton

Cancer Res. 2017 Jan 15;77(2):434-447. doi: 10.1158/0008-5472.CAN-16-2060. Epub 2016 Nov 21.

Abstract

The polo family serine threonine kinase Plk4 has been proposed as a therapeutic target in advanced cancers based on increased expression in primary human cancers, facilitation of tumor growth in murine xenograft models, and centrosomal amplification induced by its overexpression. However, both the causal link between these phenomena and the feasibility of selective Plk4 inhibition remain unclear. Here we characterize Plk4-dependent cancer cell migration and invasion as well as local invasion and metastasis of cancer xenografts. Plk4 depletion suppressed cancer invasion and induced an epithelial phenotype in poorly differentiated breast cancer cells. In an unbiased BioID screen for Plk4 interactors, we identified members of the Arp2/3 complex and confirmed a physical and functional interaction between Plk4 and Arp2 in mediating Plk4-driven cancer cell movement. This interaction is mediated through the Plk4 Polo-box 1-Polo-box 2 domain and results in phosphorylation of Arp2 at the T237/T238 activation site, which is required for Plk4-driven cell movement. Our results validate Plk4 as a therapeutic target in cancer patients and reveal a new role for Plk4 in regulating Arp2/3-mediated actin cytoskeletal rearrangement. Cancer Res; 77(2); 434-47. ©2016 AACR.

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Actin-Related Protein 2-3 Complex / metabolism*
  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Fluorescent Antibody Technique
  • Heterografts
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Immunoprecipitation
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Invasiveness / pathology*
  • Protein Serine-Threonine Kinases / metabolism*
  • Real-Time Polymerase Chain Reaction

Substances

  • Actin-Related Protein 2-3 Complex
  • PLK4 protein, human
  • Protein Serine-Threonine Kinases