Interleukin-1 Regulates the Expression of Sphingosine Kinase 1 in Glioblastoma Cells

Abstract

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.

High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease

“…Inflammation has been shown to be critical for promoting apoptosis resistance, proliferation, invasion, metastasis and secretion of proangiogenic and immunosuppressive factors in tumors of different origins, including lung (Peebles et al, 2007), prostate (Stock et al, 2008), breast (Hu and Polyak, 2008), stomach (Correa and Houghton, 2007), pancreas (Chu et al, 2007), gut (Quante and Wang, 2008) and, of course, the brain (Murat et al, 2009;Paugh et al, 2009). Thus, it is easy to imagine how the brain parenchyma of an AD patient, which is rich in proinflammatory mediators, would be a good environment for the development and progression of brain tumors.…”

“…The probability of developing either one of them increases with age (Anisimov, 2007), although for cancer this probability may experience a slight reduction after the eighth decade (Driver et al, 2008). Chronic inflammation is a common trait in the pathogenesis of both diseases (Leonard, 2007;Paugh et al 2009). Nowadays, it is widely accepted that aging is accompanied by a low-grade chronic upregulation of proinflammatory responses and, even if in many individuals this inflammation remains subclinical, in some people it may promote a number of age-associated diseases such as cancer or AD (Giunta et al, 2008).…”

A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40

“…EMSA was carried out according to the published procedures (37). Briefly, 5 g of nuclear extracts and ϳ10 fmol (10,000 cpm) of probe were used.…”

“…Nuclear Extract Preparation and EMSA-Nuclear extract from astrocytes were prepared as described (37). Doublestranded DNA fragments were labeled by filling in the 5Ј-protruding ends with Klenow enzyme using [␣-…”

The Apoptotic Mechanism of Action of the Sphingosine Kinase 1 Selective Inhibitor SKI-178 in Human Acute Myeloid Leukemia Cell Lines

“…Elevated expression of SphK1 is associated with numerous cancer types Sobue et al, 2008;Paugh et al, 2009;Knapp et al, 2010;Malavaud et al, 2010;Guan et al, 2011), and several lines of evidence link SphK1 deregulation with the progression of various hematologic malignancies (Van Brocklyn et al, 2005;Bonhoure et al, 2006;Bayerl et al, 2008;Paugh et al, 2008;Pitson et al, 2011). For example, overexpression of SphK1 has been shown to be an oncogenic event in acute erythroid leukemia progression (Le Scolan et al, 2005).…”