Activation of platelet-activating factor receptor and pleiotropic effects on tyrosine phospho-EGFR/Src/FAK/paxillin in ovarian cancer.
Activation of platelet-activating factor receptor and pleiotropic effects on tyrosine phospho-EGFR/Src/FAK/paxillin in ovarian cancer.
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DOI：
10.1158/0008-5472.can-07-5771
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Ye B
中科院分区：
文献类型：
--
作者：
Aponte M;Jiang W;Lakkis M;Li MJ;Edwards D;Albitar L;Vitonis A;Mok SC;Cramer DW;Ye B
在促炎介质中，血小板活化因子（PAF， 1- o-烷基-2-乙酰- asn -甘油-3-磷酸胆碱）是参与细胞内和细胞外通讯的主要主要和次要信使。有证据表明，PAF在癌性转化、肿瘤生长、血管生成和转移中起重要作用。然而，PAF及其受体（PAFR）及其下游信号靶点在癌症中的研究尚未深入。我们在4个正常人卵巢表面上皮细胞系（HOSE）、13个卵巢癌细胞系、84个石蜡块（n=84）和230个卵巢癌患者组织微阵列（n=230）中表征了PAFR的表达模式。PAFR在大多数非黏液型卵巢癌中均有过表达，但在HOSE和黏液型卵巢癌细胞中未见过表达。相应地，PAF仅在pafr阳性细胞（即OVCA429和OVCA432）中显著诱导细胞增殖和侵袭，而在pafr阴性卵巢细胞（HOSE和粘液性RMUG-L）中无显著诱导作用。利用PAFR特异性siRNA基因沉默探针、抗PAFR抗体和PAFR拮抗剂银果内酯b进一步证实了PAFR对细胞增殖和侵袭的依赖性。利用定量多重磷酸化抗体阵列技术，我们发现EGFR/Src/FAK/Paxilin的酪氨酸磷酸化被PAF处理协调激活，并与PI3K和cyclin D1的激活相关，PI3K和cyclin D1是细胞增殖的标志，MMP2和MMP9是细胞侵袭的标志。特异性酪氨酸Src抑制剂（PP2）可逆转阻断paf激活的癌细胞增殖和侵袭。我们认为PAFR是Src和其他信号通路的重要上游靶点，以控制paf介导的癌症进展。
Among the pro-inflammatory mediators, platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a major primary and secondary messenger involved in intra and extra cellular 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 have not been thoroughly studied in cancer. Here, we characterized the PAFR expression pattern in 4 normal human ovarian surface epithelial cell lines (HOSE), 13 ovarian cancer cell lines, paraffin blocks (n=84) and tissue microarrays (n=230) from ovarian cancer patients. Overexpression of PAFR was found in most non-mucinous 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). Dependency of cell proliferation and invasion on PAFR was further confirmed using PAFR specific siRNA 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 were coordinately activated by PAF treatment, which was correlated with activation of PI3K and cyclin D1, as markers for cell proliferation, and MMP2 and MMP9 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.