The small GTPase RhoG mediates glioblastoma cell invasion

Mol Cancer. 2012 Sep 11;11:65. doi: 10.1186/1476-4598-11-65.

Abstract

Background: The invasion of glioblastoma cells into regions of the normal brain is a critical factor that limits current therapies for malignant astrocytomas. Previous work has identified roles for the Rho family guanine nucleotide exchange factors Trio and Vav3 in glioblastoma invasion. Both Trio and Vav3 act on the small GTPase RhoG. We therefore examined the role of RhoG in the invasive behavior of glioblastoma cells.

Results: We found that siRNA-mediated depletion of RhoG strongly inhibits invasion of glioblastoma cells through brain slices ex vivo. In addition, depletion of RhoG has a marginal effect on glioblastoma cell proliferation, but significantly inhibits glioblastoma cell survival in colony formation assays. We also observed that RhoG is activated by both HGF and EGF, two factors that are thought to be clinically relevant drivers of glioblastoma invasive behavior, and that RhoG is overexpressed in human glioblastoma tumors versus non-neoplastic brain. In search of a mechanism for the contribution of RhoG to the malignant behavior of glioblastoma cells, we found that depletion of RhoG strongly inhibits activation of the Rac1 GTPase by both HGF and EGF. In line with this observation, we also show that RhoG contributes to the formation of lamellipodia and invadopodia, two functions that have been shown to be Rac1-dependent.

Conclusions: Our functional analysis of RhoG in the context of glioblastoma revealed a critical role for RhoG in tumor cell invasion and survival. These results suggest that targeting RhoG-mediated signaling presents a novel avenue for glioblastoma therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / chemistry
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Growth Processes / physiology
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism
  • Glioblastoma / chemistry
  • Glioblastoma / enzymology*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Mice
  • Neoplasm Invasiveness
  • Neuropeptides / metabolism
  • Pseudopodia / metabolism
  • Pseudopodia / ultrastructure
  • Putamen / chemistry
  • Putamen / metabolism
  • RNA, Small Interfering / genetics
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins / analysis
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*

Substances

  • Neuropeptides
  • RNA, Small Interfering
  • Rac1 protein, mouse
  • Epidermal Growth Factor
  • ErbB Receptors
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins