Human malignant
glioblastomas are highly invasive
tumors. Increased cell motility and degradation of the surrounding extracellular matrix are essential for
tumor invasion. PI3K/Akt signaling pathway emerges as a common pathway regulating cellular proliferation, migration and invasion; however, its contribution to particular process and downstream cascades remain poorly defined. We have previously demonstrated that
Cyclosporin A (CsA) affects
glioblastoma invasion in organotypic brain slices and tumorigenicity in mice. Here we show that CsA impairs migration and invasion of human
glioblastoma cells by downregulation of Akt phosphorylation. Interference with PI-3K/Akt signaling was crucial for CsA effect on invasion, because overexpression of constitutively active myr-Akt antagonized
drug action. Furthermore, the
drug was not effective in T98G
glioblastoma cells with constitutively high level of phosphorylated Akt. CsA, comparably to pharmacological inhibitors of PI3K/Akt signaling (
LY294002,
A443654), reduced motility of
glioblastoma cells, diminished MMP-2 gelatinolytic activity and MMP-2 and
MT1-MMP expression. The latter effect was mimicked by overexpression of dominant negative Akt mutants. We demonstrate that CsA and
LY294002 reduced
MMP transcription partly via modulation of IκB phosphorylation and NFκB transcriptional activity. Those effects were not mediated by inhibition of
calcineurin, a classical CsA target. Additionally, CsA reduced phosphorylation and activity of
focal adhesion kinase that was associated with rapid morphological alterations, rearrangement of lamellipodia and impairment of
MT1-MMP translocation to membrane protrusions. Our results document novel, Akt-dependent mechanisms of interference with motility/invasion of human
glioblastoma cells: through a rapid modulation of cell adhesion and
MT1-MMP translocation to membrane protrusions and delayed, partly NFκB-dependent, downregulation of MMP-2 and
MT1-MMP expression. This article is part of a Special Issue entitled: 11th European Symposium on
Calcium.