Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo

PLoS One. 2013 Dec 30;8(12):e83629. doi: 10.1371/journal.pone.0083629. eCollection 2013.

Abstract

The mechanism behind the spatiotemporal control of cancer cell dynamics and its possible association with cell proliferation has not been well established. By exploiting the intravital imaging technique, we found that cancer cell motility and invasive properties were closely associated with the cell cycle. In vivo inoculation of human colon cancer cells bearing fluorescence ubiquitination-based cell cycle indicator (Fucci) demonstrated an unexpected phenomenon: S/G2/M cells were more motile and invasive than G1 cells. Microarray analyses showed that Arhgap11a, an uncharacterized Rho GTPase-activating protein (RhoGAP), was expressed in a cell-cycle-dependent fashion. Expression of ARHGAP11A in cancer cells suppressed RhoA-dependent mechanisms, such as stress fiber formation and focal adhesion, which made the cells more prone to migrate. We also demonstrated that RhoA suppression by ARHGAP11A induced augmentation of relative Rac1 activity, leading to an increase in the invasive properties. RNAi-based inhibition of Arhgap11a reduced the invasion and in vivo expansion of cancers. Additionally, analysis of human specimens showed the significant up-regulation of Arhgap11a in colon cancers, which was correlated with clinical invasion status. The present study suggests that ARHGAP11A, a cell cycle-dependent RhoGAP, is a critical regulator of cancer cell mobility and is thus a promising therapeutic target in invasive cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle* / genetics
  • Cell Line, Tumor
  • Cell Movement* / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Enzyme Activation
  • GTPase-Activating Proteins / antagonists & inhibitors
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gene Expression
  • Gene Knockdown Techniques
  • HCT116 Cells
  • Humans
  • Neoplasm Invasiveness
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology*

Substances

  • GTPase-Activating Proteins
  • rho GTPase-activating protein

Associated data

  • GEO/GSE34940
  • GEO/GSE35279

Grant support

This work was funded by Grants-in-Aid for Scientific Research on Innovative Areas (22113007), by the FIRST Program from the Ministry of Education, Science, Sports and Culture of Japan, by grants from the International Human Frontier Science Program (RGY0077/2011); and by grants from the Takeda Science Foundation, the Cell Science Research Foundation, the Kanae Foundation for the Promotion of Medical Science, and the Nakajima Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.