Abstract
BackgroundAmong the pro-inflammatory lipid mediators, platelet-activating factor (PAF) is a major primary and secondary messenger that binds to the PAF-receptor (PAFR). Epidermal growth factor (EGF) is a polypeptide growth factor that binds to the EGF-receptor (EGFR). Evidence suggests that both PAF and EGF play a significant role in oncogenic transformation, tumor growth, neoangiogenesis and metastasis, including ovarian cancer. PAF has the potential to transactivate EGFR in ovarian cancer cells. This study explores the mechanisms involved in EGF-induced PAF production.MethodsThe effect of EGF on PAF production in ovarian cancer cells was observed using enzyme-linked immunosorbent assay. The receptors transactivation and the role of cytosolic phospholipase A2 (cPLA2) in modulating PAF production induced by EGF was assessed using pharmacological inhibitors, si-RNA knockdown, targeted gene overexpression and immunocytochemistry. The signaling pathways invovled in PAF production induced by EGF in ovarian cancer cells were assessed.ResultsWe demonstrate that EGF increases the production of PAF in CAOV3 and SKOV3 ovarian cancer cell lines. EGF induces the transactivation of PAFR, which can be blocked by an EGFR inhibitor. Inhibition of EGFR and/or PAFR blocks PAF production in response to EGF. EGF-induced PAF production involves the phosphorylation of extracellular-regulated protein kinase (ERK) and cytosolic phospholipase A2 (cPLA2). A cPLA2 inhibitor blocks EGF-induced PAF production as well as si-cPLA2, while overexpression of cPLA2 increases PAF production.ConclusionsThese results indicate that EGF stimulates PAF production in ovarian cancer cells in a manner that requires cPLA2. We have also determined that crosstalk can occur bidirectionally between EGFR and PAFR, suggesting that EGF-induced PAF production could result in positive feedback that acts on the PAF-receptor to promote ovarian cancer progression.
Highlights
Among the pro-inflammatory lipid mediators, platelet-activating factor (PAF) is a major primary and secondary messenger that binds to the PAF-receptor (PAFR)
Effects of Epidermal growth factor (EGF) on PAF production in ovarian cancer cells As shown in Figure 1, in CAOV3 ovarian cancer cell lines, extracellular EGF caused a significant rise in the PAF released from 0.5 ng/ml to 100 ng/ml; while in SKOV3 ovarian cancer cell lines, ext racellular EGF caused a significant rise in the PAF release from 1 ng/ml to 100 ng/ml
Akt and extracellular-regulated protein kinase (ERK) lie downstream of activated EGFR and PAFR, and ERK is required for activation of cytosolic phospholipase A2 (cPLA2) We investigated the signaling pathway downstream of activated EGFR and PAFR in ovarian cancer cells to elucidate the mechanisms involved in EGF-induced PAF production
Summary
Among the pro-inflammatory lipid mediators, platelet-activating factor (PAF) is a major primary and secondary messenger that binds to the PAF-receptor (PAFR). Chronic inflammatory microenvironments have been suggested as the major predisposing factor for ovarian and other cancers [1] Lipid mediators such as lysophosphatidic acid (LPA) and prostaglandins (PGs), with their specific receptors and pathways, have been shown to play a critical role in cancer initiation and progression [2,3,4]. Lyso-PAF acetyltransferase converts lysoPAF into PAF and PAF activates the PAF-receptor (PAFR), a member of the superfamily of G proteincoupled receptors [8,9] These events are thought to play an important role in the oncogenic transformation [10], proliferation [11] and metastasis [12] of several types of cancers, including ovarian cancers. There maybe a possibility that PAF acts as an autocrine growth factor to promote ovarian cancer progression
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