INVESTIGADORES
ALVAREZ Silvina Monica
artículos
Título:
SPHINGOSINE-1-PHOSPHATE AND INTERLEUKIN-1 INDEPENDENTLY REGULATE PLASMINOGEN ACTIVATOR INHIBITOR-1 AND UROKINASE-TYPE PLASMINOGEN ACTIVATOR RECEPTOR EXPRESSION IN GLIOBLASTOMA CELLS: IMPLICATION FOR INVASIVNESS
Autor/es:
BRYAN L; PAUGH BS; KAPITONOV D; WILCZINSKA KM; ALVAREZ SM; SINGH SK; MILSTIEN S; SPIEGEL S; KORDULA T
Revista:
MOLECULAR CANCER RESEARCH
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Año: 2008 vol. 6 p. 1469 - 1477
ISSN:
1541-7786
Resumen:
Glioblastoma multiforme is an invasive primary brain
tumor, which evades the current standard treatments.
The invasion of glioblastoma cells into healthy brain
tissue partly depends on the proteolytic and
nonproteolytic activities of the plasminogen activator
system proteins, including the urokinase-type
plasminogen activator (uPA), plasminogen activator
inhibitor 1 (PAI-1), and a receptor for uPA (uPAR). Here
we show that sphingosine-1-phosphate (S1P) and the
inflammatory mediator interleukin-1 (IL-1) increase the
mRNA and protein expression of PAI-1 and uPAR and
enhance the invasion of U373 glioblastoma cells.
Although IL-1 enhanced the expression of sphingosine
kinase 1 (SphK1), the enzyme that produces S1P,
down-regulation of SphK1 had no effect on the
IL-1induced uPAR or PAI-1 mRNA expression,
suggesting that these actions of IL-1 are independent of
S1P production. Indeed, the S1P-induced mRNA
expression of uPAR and PAI-1 was blocked by the S1P2
receptor antagonist JTE013 and by the down-regulation
of S1P2 using siRNA. Accordingly, the inhibition
of mitogen-activated protein kinase/extracellular
signalregulated kinase kinase 1/2 and Rho-kinase, two
downstream signaling cascades activated by S1P2,
blocked the activation of PAI-1 and uPAR mRNA
expression by S1P. More importantly, the attachment of
glioblastoma cells was inhibited by the addition of
exogenous PAI-1 or siRNA to uPAR, whereas the
invasion of glioblastoma cells induced by S1P or IL-1
correlated with their ability to enhance the expression of
PAI-1 and uPAR. Collectively, these results indicate that
S1P and IL-1 activate distinct pathways leading to the
mRNA and protein expression of PAI-1 and uPAR, which
are important for glioblastoma invasiveness.