SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions

Mol Cancer Res. 2004 Nov;2(11):595-605.


Malignant glioma is the major brain tumor in adults and has a poor prognosis. The failure to control invasive cell subpopulations may be the key reason for local glioma recurrence after radical tumor resection and may contribute substantially to the failure of the other treatment modalities such as radiation therapy and chemotherapy. As a model for this invasion, we have implanted spheroids from a human glioma cell line (U251) in three-dimensional collagen type I matrices, which these cells readily invade. We first observed that the Src family kinase-specific pharmacologic inhibitors PP2 and SU6656 significantly inhibited the invasion of the cells in this assay. We confirmed this result by showing that expression of two inhibitors of Src family function, dominant-negative-Src and CSK, also suppressed glioma cell invasion. To characterize this effect at the level of the cytoskeleton, we used fluorescent time-lapse microscopy on U251 cells stably expressing a YFP-actin construct and observed a rapid change in actin dynamics following addition of PP2 in both two-dimensional and three-dimensional cultures. In monolayer cultures, PP2 caused the disappearance of peripheral membrane ruffles within minutes. In three-dimensional cultures, PP2 induced the loss of actin bursting at the leading tip of the invadopodium. The inhibition of Src family activity is thus a potential therapeutic approach to treat highly invasive malignant glioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism
  • Actins / metabolism*
  • Animals
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / physiopathology
  • CSK Tyrosine-Protein Kinase
  • Cell Line, Tumor
  • Cell Surface Extensions / drug effects
  • Cell Surface Extensions / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism*
  • Glioblastoma / physiopathology
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Models, Biological
  • Neoplasm Invasiveness / physiopathology*
  • Phosphotransferases / genetics
  • Phosphotransferases / metabolism
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Rats
  • Spheroids, Cellular
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*


  • AG 1879
  • Actins
  • Enzyme Inhibitors
  • Indoles
  • Proto-Oncogene Proteins
  • Pyrimidines
  • SU 6656
  • Sulfonamides
  • Phosphotransferases
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human