Linnea M. Baudhuin

Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1.

Sphingosylphosphorylcholine (SPC) is a bioactive lipid that acts as an intracellular and extracellular signalling molecule in numerous biological processes. Many of the cellular actions of SPC are believed to be mediated by the activation of unidentified G-protein-coupled receptors. Here we show that SPC is a high-affinity ligand for an orphan receptor, ovarian cancer G-protein-coupled receptor 1 (OGR1). In OGR1-transfected cells, SPC binds to OGR1 with high affinity (Kd = 33.3 nM) and high specificity and transiently increases intracellular calcium. The specific binding of SPC to OGR1 also activates p42/44 mitogen-activated protein kinases (MAP kinases) and inhibits cell proliferation. In addition, SPC causes internalization of OGR1 in a structurally specific manner.

Sphingosine‐1‐phosphate modulates growth and adhesion of ovarian cancer cells

Sphingosine‐1‐phosphate (S1P) is a bioactive lipid molecule. It stimulates the growth of some cells, but inhibits the growth of others. In this study, we describe the detection of sub‐μM to μM concentrations of S1P in the ascitic fluids of patients with ovarian cancer. In ovarian cancer cells cultured in vitro, S1P exhibited a dual effect on growth and/or survival. S1P (10 μM) induced cell death when cells were in suspension but stimulated cell growth when cells were attached. The calcium‐dependent induction of cell death by S1P is apparently associated with its inhibitory effect on cell attachment and cell adhesion. S1P (10–30 μM) also induced calcium‐dependent cell‐cell aggregation.

S1P3-mediated Akt activation and cross-talk with platelet-derived growth factor receptor (PDGFR)

Akt plays a pivotal role in cell survival and tumorigenesis. We investigated the potential interaction between sphingosine‐1‐phosphate (S1P) and platelet‐derived growth factor (PDGF) in the Akt signaling pathway. Using mouse embryonic fibroblasts (MEFs) from S1P receptor knockout mice, we show here that S1P3 was required for S473 phosphorylation of Akt by S1P. In addition, S1P‐stimulated activation of Akt, but not ERK, was blocked by a PDGF receptor (PDGFR)‐specific inhibitor, AG1296, suggesting a S1P3‐mediated specific crosstalk between the Akt signaling pathways of S1P and PDGFR in MEFs. We investigated this crosstalk under different conditions and found that both Akt and ERK activation induced by S1P, but not lysophosphatidic acid (LPA), in HEY ovarian cancer cells required PDGFR but not epidermal growth factor receptor (EGFR) or insulin‐like growth factor‐I receptor (IGFR). Importantly, S1P induced a Gi‐dependent tyrosine phosphorylation of PDGFR in HEY cells. This dependence on PDGFR in S1P‐induced Akt activation was also observed in A2780, T47D, and HMEC‐1 cells (which express S1P3), but not in PC‐3 or GI‐101A cells (which do not express S1P3), further supporting that S1P3 mediates the crosstalk between S1P and PDGFR. This is the first report demonstrating a unique interaction between S1P3 and PDGFR, in addition to demonstrating a specific role for S1P3 in S1P‐induced Akt activation.

Unfolding the pathophysiological role of bioactive lysophospholipids.

Lysophospholipids (LPLs), including glycerol- and sphingoid-based lipids, stimulate cell signaling and play important pathophysiological roles in humans and other animals. These LPLs include lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC). Analyses of LPLs in human body fluids from subjects with different pathophysiological conditions reveal not only the relevance of LPLs in human diseases, but also their potential application as biomarkers and/or therapeutic targets. In recent years, the identification and/or characterization of the plasma membrane receptors for LPLs and enzymes regulating the metabolism of LPLs have greatly facilitated our understanding of their role and signaling properties. In vitro and in vivo functional and signaling studies have revealed the broad and potent biological effects of LPLs and the mechanisms of LPL actions in different cellular systems. Development of specific antagonists for each of the LPL receptors will provide powerful tools for dissecting signaling pathways mediated by receptor subtypes. More importantly, these antagonists may serve as therapeutics for relevant diseases. Genetic depletion of LPL receptors in mice has provided and will continue to provide critical information on the pathophysiological roles of LPL receptors. It is important to further evaluate the significance of targeting these bioactive LPL receptors, their downstream signaling molecules, and/or metabolic enzymes in the treatment of cancers and other diseases.

The role and clinical applications of bioactive lysolipids in ovarian cancer

Objective: To review the current understanding of the role of bioactive lysolipids in ovarian cancer and their potential clinical applications. Methods: A MEDLINE search and our own work, including some unpublished work, are the major sources of the review. The MEDLINE search terms used included lysophosphatidic acid, lysophophatidylcholine (LPC), lysophosphatidylinositol (LPI), sphingosine-1-phosphate, and sphingosylphosphorylcholine (SPC). Results: Elevated lysolipid levels were detected in plasma and ascites samples from patients with ovarian cancer compared with samples from healthy controls or patients with nonmalignant diseases. These lysolipids regulate growth adhesion, production of angiogenic factors, and chemotherapeutic drug resistance in ovarian cancer cells. Ovarian cancer cells were likely to be at least one of the sources for elevated lysolipid levels in the blood and ascites of patients with ovarian cancer. Conclusions: Bioactive lysolipid levels might be sensitive markers for detecting gynecologic cancers, particularly ovarian cancer. The prognostic value of lysolipids in ascites is worth further investigation. Bioactive lysolipid molecules can affect both the proliferative and metastatic potentials of ovarian cancer cells; therefore, regulation of the production or degradation of these lipids and interception of the interaction between these lipids and their receptors could provide novel and useful preventative or therapeutic measures.

Erratum: Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor1. (Nature Cell Biology (2000) vol. 2 (261-267))

Owing to the serious concerns about the validity of the data published in the paper, the authors would like to retract this paper. All authors, apart from Dr. Kui Zhu, have signed this retraction. Dr. Zhu did not return a signature.

SPC/LPC Receptors

Among LPLs, the biological effects and signaling mechanisms of lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), and their receptors (LPA 1–3 and S1P 1–5 ) have been studied most extensively. The signaling mechanisms of their corresponding choline derivatives, lysophosphatidylcholine (LPC) and sphingosylphosphorylcholine (SPC), however, have been examined to a much lower extent, although their extracellular existence and evidence of their signaling properties have long been recognized. Addition of a positively charged choline group to the negatively charged phosphate group provides LPC and SPC with zwitterionic and detergent-like properties. In fact, LPC is cell lytic at concentrations >30 μM when bovine serum albumin (BSA) is absent. Moreover, the specific receptors for LPC and SPC were not previously identified. Thus, controversy has arisen as to whether LPC, and possibly SPC, act as specific signaling molecules or molecules modulatingcellular functions nonspecifically, and whether their actions are receptor-mediated. This situation has been changed recently with the identification of three G-protein-coupled receptors (GPCRs)—OGRl, GPR4, and G2A—as receptors for LPC and SPC. These discoveries provide an intriguing and novel opportunity to study the pathophysiological and functional roles of SPC, LPC, and their receptors.