Invasion of
tumor cells is the primary cause of therapeutic failure in the treatment of malignant
chondrosarcomas.
Glial cell-derived neurotrophic factor (
GDNF) plays a crucial role in migration and
metastasis of human
cancer cells.
Integrins are the major adhesive molecules in mammalian cells. Here we found that
GDNF directed the migration and increased cell surface expression of alphav and
beta3 integrin in human
chondrosarcoma cells. Pretreated of JJ012 cells with
MAPK kinase (
MEK) inhibitors
PD98059 or
U0126 inhibited the
GDNF-mediated migration and
integrin expression. Stimulation of cells with
GDNF increased the phosphorylation of
MEK and extracellular signal-regulating
kinase (ERK). In addition,
NF-kappaB inhibitor (
PDTC) or IkappaB
protease inhibitor (
TPCK) also inhibited
GDNF-mediated cells migration and
integrin up-regulation. Stimulation of cells with
GDNF induced
IkappaB kinase (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-
luciferase activity. Furthermore, the
GDNF-mediated increasing of kappaB-
luciferase activity was inhibited by
PD98059,
U0126,
PDTC and
TPCK or
MEK, ERK, IKKalpha, and IKKbeta mutants. Taken together, these results suggest that the
GDNF acts through
MEK/ERK, which in turn activates IKKalpha/beta and
NF-kappaB, resulting in the activations of
alphavbeta3 integrin and contributing the migration of human
chondrosarcoma cells.