Enhanced phosphorylation of sphingosine and ceramide sustains the exuberant proliferation of endothelial progenitors in Kaposi sarcoma

Abstract

Endothelial colony-forming cells (ECFCs), a unique endothelial stem cell population, are highly increased in the blood of Kaposi sarcoma (KS) patients. KS-derived ECFCs (KS-ECFCs) are also endowed with increased proliferative and vasculogenic potential, thus suggesting that they may be precursors of KS spindle cells. However, the mechanisms underlying the increased proliferative activity of KS-ECFCs remain poorly understood. Sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) are metabolically interconnected sphingoid mediators crucial to cell proliferation. Here, we investigated the metabolism, release, and proliferative effects of S1P and C1P in KS-ECFCs compared with control ECFCs (Ct-ECFCs). Metabolic studies by cell labeling, chromatographic analyses, and digital autoradiography revealed that S1P and C1P biosynthesis and S1P secretion are all efficient processes in KS-ECFCs, more efficient in KS-ECFCs than Ct-ECFCs. Quantitative PCR analyses demonstrated a significantly higher ceramide kinase and sphingosine kinase-2 expression in KS-ECFCs. Notably, also the expression of S1P1 and S1P3 receptors was augmented in KS-ECFCs. Accordingly, treatment with exogenous C1P or S1P induced a significant, concentration-dependent stimulation of KS-ECFC proliferation, but was almost completely ineffective in Ct-ECFCs. Hence, we identified C1P and S1P as autocrine/paracrine proliferative signals in KS-ECFCs. A better understanding of the mechanisms that enhance S1P/C1P formation in KS-ECFCs may yield effective therapeutic modalities.

The synthetic phospholipid C8-C1P determines pro-angiogenic and pro-reparative features in human macrophages restraining the proinflammatory M1-like phenotype

“…Moreover, the anti-apoptotic pathway induced by C8-C1P involved the up-regulation of BCL-2 and ERK 1/2 signaling. These results are in concordance with previous reports showing that natural C16-C1P is able to upregulate another BCL-2 subfamily member -BCL-XLin apoptotic macrophages (30), and that the phospho-sphingolipid C1P triggers ERK and AKT signaling pathways in several cell types (9,29,31,32). Additionally, Jung et al showed that C2, C6, and C8 ceramides as well as C8 ceramide-1-phosphate inhibited iNOS and proinflammatory cytokines in LPS-stimulated BV2 microglial cells and rat primary microglia.…”

“…A well-reported property of C1P is its ability to induce cell survival, counteract apoptotic stressors, and induce proliferation in different models (8,28,29). Here we showed that both types of phospholipids, the natural C16-C1P and the synthetic C8-C1P, promote antiapoptotic activity after serum deprivation in freshly isolated human CD14 + monocytes.…”

Implication of Ceramide Kinase/C1P in Cancer Development and Progression

“…Interestingly, endothelial colony-forming cells, a unique endothelial stem cell population, are highly increased in the blood of Kaposi sarcoma patients and have the ability to efficiently produce high levels of C1P (and S1P), a fact that significantly contributes to their increased proliferative properties. Additionally, exogenous C1P and S1P were found to stimulate proliferation of these cells [ 84 ], suggesting that both bioactive sphingolipids are relevant for development of Kaposi sarcoma; targeting C1P and S1P signaling may turn out to be a useful therapeutic approach to treat the disease.…”

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

“…C1P-enhanced pancreatic tumor cell migration and invasion are dependent upon PI3K, Akt1, mTOR1, ERK1-2, and RhoA/ROCK signaling pathways [39]. CerK activity is required in the proliferation of neuroblastoma cells [40], of breast cancer cells [41], and of Kaposi sarcoma stem cells [42]. In metastatic breast cancer cells, CerK is upregulated and contributes to the migration and invasion through PI3K/Akt/Rho kinase activation [43].…”