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

Author(s): Yi Yu ¹ ^, ² ^, ³ , Xiaoyan Zhang ¹ ^, ² ^, ³ , Shanshan Hong ¹ ^, ² ^, ³ , Mingxing Zhang ¹ ^, ² ^, ³ , Qingqing Cai ¹ ^, ² ^, ³ , Wei Jiang ¹ ^, ² ^, ³ ^, , Congjian Xu ¹ ^, ² ^, ³ ^, ⁴ ^,

Publication date (Electronic): 11 April 2014

Journal: Journal of Ovarian Research

Publisher: BioMed Central

Keywords: Ovarian cancer, EGF, EGF-receptor, PAF-receptor, ERK, cPLA2

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Abstract

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 A ₂ (cPLA ₂) 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 A ₂ (cPLA ₂). A cPLA ₂ inhibitor blocks EGF-induced PAF production as well as si-cPLA ₂, while overexpression of cPLA ₂ increases PAF production.

Conclusions

These results indicate that EGF stimulates PAF production in ovarian cancer cells in a manner that requires cPLA ₂. 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.

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Most cited references 32

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G-protein-coupled receptors and cancer.

Robert Dorsam, J. Silvio Gutkind (2007)

G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment.

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John Mendelsohn, José Baselga (2003)

The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor overexpression correlates with a more aggressive clinical course. Taken together, these observations indicate that the EGFR is a promising target for cancer therapy. Monoclonal antibodies directed at the ligand-binding extracellular domain and low-molecular weight inhibitors of the receptor's tyrosine kinase are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. They also enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non-small-cell lung cancer, head and neck cancer, ovarian carcinoma, and renal cell carcinoma. Although antitumor activity is significant, responses have been seen in only a minority of the patients treated. In some clinical trials, anti-EGFR agents enhanced the effects of conventional chemotherapy and radiation therapy. Ongoing research efforts are directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies.

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Phospholipase A2 (PLA2) comprises a superfamily of enzymes that hydrolyse the ester bond of phospholipids at the sn-2 position. Among the members of this superfamily, cytosolic PLA2 has attracted attention because it preferentially hydrolyses arachidonoyl phospholipids and is activated by submicromolar concentrations of Ca2+ ions and by phosphorylation by mitogen-activated protein kinases (MAP kinases). Here we investigate the function of cytosolic PLA2 in vivo by using homologous recombination to generate mice deficient in this enzyme. These mice showed a marked decrease in their production of eicosanoids and platelet-activating factor in peritoneal macrophages. Their ovalbumin-induced anaphylactic responses were significantly reduced, as was their bronchial reactivity to methacholine. Female mutant mice failed to deliver offspring, but these could be rescued by administration of a progesterone-receptor antagonist to the mother at term. Considered together with previous findings, our results indicate that cytosolic PLA2 plays a non-redundant role in allergic responses and reproductive physiology.

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Author and article information

Contributors

Yi Yu

Xiaoyan Zhang

Shanshan Hong

Mingxing Zhang

Qingqing Cai

Wei Jiang

Congjian Xu

Journal

Journal ID (nlm-ta): J Ovarian Res

Journal ID (iso-abbrev): J Ovarian Res

Title: Journal of Ovarian Research

Publisher: BioMed Central

ISSN (Electronic): 1757-2215

Publication date Collection: 2014

Publication date (Electronic): 11 April 2014

Volume: 7

Page: 39

Affiliations

[1 ]Obstetrics and Gynecology Hospital, Fudan University, No.419 Fang-Xie Road, Shanghai 200011, People’s Republic of China

[2 ]Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, No.138 Yi-Xueyuan Road, Shanghai 200032, People’s Republic of China

[3 ]Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, No. 413 Zhao-Jiabang Road, Shanghai 200011, People’s Republic of China

[4 ]Institute of Biomedical Sciences, Fudan University, No.138 Yi-Xueyuan Road, Shanghai 200032, People’s Republic of China

Article

Publisher ID: 1757-2215-7-39

DOI: 10.1186/1757-2215-7-39

PMC ID: 4005630

PubMed ID: 24721622

SO-VID: 4b1fc460-a3d1-4c6c-95f4-83685e088387

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 March 2014

Date accepted : 8 April 2014

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