INVESTIGADORES
ALVAREZ Silvina Monica
artículos
Título:
INTERLEUKIN-1 REGULATES THE EXPRESSION OF SPHINGOSINE KINASE 1 IN GLIOBLASTOMA CELLS
Autor/es:
PAUGH BS; BRYAN L; PAUGH SW; WILCZINKA KM; ALVAREZ SILVINA M; SINGH SK; KAPITONOV D; ROKITA H; WRIGHT S; GRISWOLD-PRENNER I; MILSTIEN S; SPIEGEL S; KORDULA T
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Año: 2009 vol. 284 p. 3408 - 3417
ISSN:
0021-9258
Resumen:
Chronic inflammation and inflammatory cytokines have
recently been implicated in the development and progression of
various types of cancer. In the brain, neuroinflammatory cytokines
affect the growth and differentiation of both normal and
malignant glial cells, with interleukin 1 (IL-1) shown to be
secreted by the majority of glioblastoma cells. Recently, elevated
levels of sphingosine kinase 1 (SphK1), but not SphK2, were
correlated with a shorter survival prognosis for patients with
glioblastoma multiforme. SphK1 is a lipid kinase that produces
the pro-growth, anti-apoptotic sphingosine 1-phosphate, which
can induce invasion of glioblastoma cells. Here, we show that the
expression of IL-1 correlates with the expression of SphK1 in
glioblastoma cells, and neutralizing anti-IL-1 antibodies inhibit
both the growth and invasion of glioblastoma cells. Furthermore,
IL-1 up-regulates SphK1 mRNA levels, protein expression,
and activity in both primary human astrocytes and various
glioblastoma cell lines; however, it does not affect SphK2
expression. The IL-1-induced SphK1 up-regulation can be
blocked by the inhibition of JNK, the overexpression of the
dominant-negative c-Jun(TAM67), and the down-regulation
of c-Jun expression by small interference RNA. Activation of
SphK1 expression by IL-1 occurs on the level of transcription
and is mediated via a novel AP-1 element located within the
first intron of the sphk1 gene. In summary, our results suggest
that SphK1 expression is transcriptionally regulated by IL-1
in glioblastoma cells, and this pathway may be important
in regulating survival and invasiveness of glioblastoma
cells.