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Journal of Experimental and Clinical Cancer Research

, 33:85

First Online: 28 September 2014Received: 22 July 2014Accepted: 24 September 2014DOI: 10.1186-s13046-014-0085-6

Cite this article as: Yu, Y., Zhang, M., Zhang, X. et al. J Exp Clin Cancer Res 2014 33: 85. doi:10.1186-s13046-014-0085-6

Abstract

BackgroundWe 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.

MethodsExpression 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.

ResultsOur 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-β 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.

ConclusionsThe 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.

KeywordsPlatelet-activating factor receptor Epidermal growth factor receptor Ovarian cancer cells Transactivation AbbreviationsPAFPlatelet-activating factor

PAFRPAF-receptor

EGFEpidermal growth factor

EGFREGF-receptor

HB-EGFHeparin-binding epidermal growth factor

GPCRG-protein coupled receptor GPCR family

PLCβPhospholipase C-β

ERKExtracellular-regulated protein kinase

InsP3Inositol trisphosphat

DAGDiacylglycerol

ADAMA disintegrin and metalloproteinase

MMPMetalloproteinase

AG1478An EGFR-specific tyrosine kinase inhibitor

WEB2086A specific PAFR antagonist

Electronic supplementary materialThe online version of this article doi:10.1186-s13046-014-0085-6 contains supplementary material, which is available to authorized users.

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Autor: Yi Yu - Mingxing Zhang - Xiaoyan Zhang - Qingqing Cai - Zhiling Zhu - Wei Jiang - Congjian Xu

Fuente: https://link.springer.com/







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