A virally encoded GPCR drives glioblastoma through feed-forward activation of the SK1-S1P ₁ signaling axis

Abstract

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 (S1P 1 )], 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.

G protein-coupled receptors: a gateway to targeting oncogenic EVs?

“…Aside from regulating many physiological processes, dysregulated GPCR expression and/or signaling has been linked to several hallmarks of cancer (reviewed in [35] ), including proliferation and survival [36] , invasion and metastasis [37] , angiogenesis [38] , and immune cell evasion [39] . For instance, in breast cancer, the chemokine receptor CXCR4 is overexpressed and its natural ligand, CXCL12, was shown to be highly secreted near the organs that are the metastatic destination of the tumor cells, indicative of a key role in metastatic colonization [37] .…”

Sphingolipid Signaling and Complement Activation in Glioblastoma: A Promising Avenue for Therapeutic Intervention

“…The human cytomegalovirus-encoded G protein-coupled receptor (GPCR), US28, was reported to promote U251 glioblastoma malignancy by stimulating SPHK1 function to release more S1P, which signals via S1PR1 using in vitro assays ( Figure 4 ). The SPHKI/S1P/S1PR1 signaling activates AKT, JAK2/STAT3, and cMYC and enhances the levels of the cancerous inhibitor of protein phosphatase 2A (CIP2A) downstream to promote the pro-survival phenotype in glioblastoma cells [ 97 ]. Using xenogeneic glioma mouse models and in vitro assays, Arseni et al showed that SPHK1/S1P/S1PR signaling axis consistently stimulates the enhanced recruitment of tumor-associated macrophages (TAMs), triggering pro-tumorigenic phenotype in glioblastoma cells [ 98 ].…”