Paugh Barbara S, Bryan Lauren, Paugh Steven W, Wilczynska Katarzyna M, Alvarez Silvina M, Singh Sandeep K, Kapitonov Dmitri, Rokita Hanna, Wright Sarah, Griswold-Prenner Irene, Milstien Sheldon, Spiegel Sarah, Kordula Tomasz
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
J Biol Chem. 2009 Feb 6;284(6):3408-17. doi: 10.1074/jbc.M807170200. Epub 2008 Dec 11.
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.
慢性炎症和炎性细胞因子最近被认为与各类癌症的发生和发展有关。在大脑中，神经炎性细胞因子影响正常和恶性胶质细胞的生长与分化，其中白细胞介素1（IL-1）被证明由大多数胶质母细胞瘤细胞分泌。最近，多形性胶质母细胞瘤患者中，鞘氨醇激酶1（SphK1）水平升高而非SphK2水平升高与较短的生存预后相关。SphK1是一种脂质激酶，可产生促生长、抗凋亡的1-磷酸鞘氨醇，它能诱导胶质母细胞瘤细胞的侵袭。在此，我们表明IL-1的表达与胶质母细胞瘤细胞中SphK1的表达相关，中和性抗IL-1抗体可抑制胶质母细胞瘤细胞的生长和侵袭。此外，IL-1上调原代人星形胶质细胞和各种胶质母细胞瘤细胞系中SphK1的mRNA水平、蛋白表达及活性；然而，它不影响SphK2的表达。IL-1诱导的SphK1上调可被JNK抑制、显性负性c-Jun（TAM67）的过表达以及小干扰RNA介导的c-Jun表达下调所阻断。IL-1对SphK1表达的激活发生在转录水平，并通过位于sphk1基因第一内含子内的一个新的AP-1元件介导。总之，我们的结果表明，在胶质母细胞瘤细胞中，SphK1的表达受IL-1转录调控，该途径可能在调节胶质母细胞瘤细胞的存活和侵袭性方面具有重要作用。
