Epidermal growth factor induces platelet-activating factor production through receptors transactivation and cytosolic phospholipase A2 in ovarian cancer cells

Journal of Ovarian Research

Congjian Xu¹  Wei Jiang²  Qingqing Cai²  Mingxing Zhang²  Shanshan Hong²  Xiaoyan Zhang²  Yi Yu² 

[1] Institute of Biomedical Sciences, Fudan University, No.138 Yi-Xueyuan Road, Shanghai 200032, People’s Republic of China;Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, No. 413 Zhao-Jiabang Road, Shanghai 200011, People’s Republic of China

关键词: cPLA₂;    ERK;    PAF-receptor;    EGF-receptor;    EGF;    Ovarian cancer;   

Others  :  801668
DOI  :  10.1186/1757-2215-7-39

 received in 2014-03-05, accepted in 2014-04-08,  发布年份 2014

【 摘 要 】

Background

Among 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.

Methods

The 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.

Results

We 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.

Conclusions

These 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.

【 授权许可】

   
2014 Yu et al.; licensee BioMed Central Ltd.

【 图 表 】

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