Activation of Platelet-Activating Factor Receptor and Pleiotropic Effects on Tyrosine Phospho-EGFR/Src/FAK/Paxillin in Ovarian Cancer

Abstract

Among the proinflammatory mediators, platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a major primary and secondary messenger involved in intracellular and extracellular communication. Evidence suggests that PAF plays a significant role in oncogenic transformation, tumor growth, angiogenesis, and metastasis. However, PAF, with its receptor (PAFR) and their downstream signaling targets, has not been thoroughly studied in cancer. Here, we characterized the PAFR expression pattern in 4 normal human ovarian surface epithelial (HOSE) cell lines, 13 ovarian cancer cell lines, paraffin blocks (n = 84), and tissue microarrays (n = 230) from patients with ovarian cancer. Overexpression of PAFR was found in most nonmucinous types of ovarian cancer but not in HOSE and mucinous cancer cells. Correspondingly, PAF significantly induced cell proliferation and invasion only in PAFR-positive cells (i.e., OVCA429 and OVCA432), but not in PAFR-negative ovarian cells (HOSE and mucinous RMUG-L). The dependency of cell proliferation and invasion on PAFR was further confirmed using PAFR-specific small interfering RNA gene silencing probes, antibodies against PAFR and PAFR antagonist, ginkgolide B. Using quantitative multiplex phospho-antibody array technology, we found that tyrosine phosphorylation of EGFR/Src/FAK/paxilin was coordinately activated by PAF treatment, which was correlated with the activation of phosphatidylinositol 3-kinase and cyclin D1 as markers for cell proliferation, as well as matrix metalloproteinase 2 and 9 for invasion. Specific tyrosine Src inhibitor (PP2) reversibly blocked PAF-activated cancer cell proliferation and invasion. We suggest that PAFR is an essential upstream target of Src and other signal pathways to control the PAF-mediated cancer progression. [Cancer Res 2008;68(14):5839-48]

Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells

“…Dasatinib and PP2 produced similar results in studies conducted in MDA-MB-231, W53 lymphoid cells, MCF7 and in ovarian cancer cells [2,11,30,35]. Also, interfering SFKs functionality by conditional expression of SrcDN in MCF7 cells causes accumulation in G1 and increased p27…”

“…In MDA-MB-231 and BT-549, inhibition of SFKs by SU6656 suppresses invadopodia formation while enhances tubulin-based microtentacle, effects associated with reduced cellular invasion [33]. PP2 also inhibits invasion in MDA-MB-231 [34] and ovarian cancer cells [35].…”

SIRPα1 receptors interfere with the EGFRvIII signalosome to inhibit glioblastoma cell transformation and migration

“…On the other hand, increased FAK expression and activity has been reported to enhance transformation, invasion and malignant tumor phenotype (Benlimame et al, 2005;Madan et al, 2006;Aponte et al, 2008;Dai et al, 2008;Luo et al, 2009). FAK has also been shown to activate the MAPK pathway through multiple pathways, including through the Src/SHP-2/SIRPa1(SHPS-1) axis (Takeda et al, 1998;Tsuda et al, 1998).…”

Feed-Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial–Mesenchymal Transition in Non–Small Cell Lung Cancer

“…Inhibition of PAFR activity by its specific inhibitor can effectively block the breast cancer cell growth and invasion in vitro (8). Disruption of the PAF/PAFR interaction or knockdown of the expression of PAFR can effectively block the invasion of ovarian tumor cells (9). However, the biologic roles of PAFR in NSCLC metastasis have not been investigated.…”