| Autor: |
Bergkamp, Nick D., van Senten, Jeffrey R., Brink, Hendrik J., Bebelman, Maarten P., van den Bor, Jelle, Çobanoğlu, Tuğçe S., Dinkla, Kasper, Köster, Johannes, Klau, Gunnar, Siderius, Marco, Smit, Martine J. |
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| Zdroj: |
Science Signaling; 8/15/2023, Vol. 16 Issue 798, p1-16, 16p |
| Abstrakt: |
The G protein–coupled receptor (GPCR) US28 encoded by the human cytomegalovirus (HCMV) is associated with accelerated progression of glioblastomas, aggressive brain tumors with a generally poor prognosis. Here, we showed that US28 increased the malignancy of U251 glioblastoma cells by enhancing signaling mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that stimulates oncogenic pathways in glioblastoma. US28 expression increased the abundance of the key components of the S1P signaling axis, including an enzyme that generates S1P [sphingosine kinase 1 (SK1)], an S1P receptor [S1P receptor 1 (S1P1)], and S1P itself. Enhanced S1P signaling promoted glioblastoma cell proliferation and survival by activating the kinases AKT and CHK1 and the transcriptional regulators cMYC and STAT3 and by increasing the abundance of cancerous inhibitor of PP2A (CIP2A), driving several feed-forward signaling loops. Inhibition of S1P signaling abrogated the proliferative and anti-apoptotic effects of US28. US28 also activated the S1P signaling axis in HCMV-infected cells. This study uncovers central roles for S1P and CIP2A in feed-forward signaling that contributes to the US28-mediated exacerbation of glioblastoma. Editor's summary: US28 is a GPCR encoded by the β-herpesvirus human cytomegalovirus (HCMV) whose expression is associated with glioblastoma progression and contributes to the tumorigenic properties of HCMV. Bergkamp et al. showed that US28 expression was associated with increased signaling through the sphingosine-1-phosphate (S1P) pathway, a potent driver of gliomagenesis. US28 stimulated sphingosine kinase 1, which generates S1P, and activated STAT3 signaling in an S1P-dependent manner, leading to the increased proliferation and survival of glioblastoma cells. This work provides insight into how manipulating host cell signaling enables HCMV to promote glioblastoma progression. —Amy E. Baek [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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