Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

Journal of Experimental & Clinical Cancer Research

Congjian Xu¹  Wei Jiang²  Zhiling Zhu²  Qingqing Cai²  Xiaoyan Zhang²  Mingxing Zhang²  Yi Yu² 

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

关键词: Transactivation;    Ovarian cancer cells;    Epidermal growth factor receptor;    Platelet-activating factor receptor;   

Others  :  1145583
DOI  :  10.1186/s13046-014-0085-6

 received in 2014-07-22, accepted in 2014-09-24,  发布年份 2014

【 摘 要 】

Background

We previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer.

Methods

Expression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay.

Results

Our data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-? and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner.

Conclusions

The results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.

【 授权许可】

   
2014 Yu et al.; licensee BioMed Central Ltd.

【 图 表 】

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