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Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells

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Abstract

Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been involved in the pathogenesis of prostate cancer (PC). HIF-1α, which is up-regulated by PGE2 in LNCaP cells and PC3 cells, has been shown to contribute to metastasis and chemo-resistance of castrate-resistant PC (a lethal form of PC) and to promote in PC cells migration, invasion, angiogenesis and chemoresistance. The selective blockade of PGE2-EP2 signaling pathway in PC3 cells results in inhibition of cancer cell proliferation and invasion. PGE2 affects many mechanisms that have been shown to play a role in carcinogenesis such as proliferation, apoptosis, migration, invasion and angiogenesis. Recently, we have found in PC3 cells that most of these PGE2-induced cancer-related features are due to intracellular PGE2 (iPGE2). Here, we aimed to study in PC3 cells the role of iPGE2-intracellular EP2 (iEP2)-HIF-1α signaling in several events linked to PC progression using an experimental approach involving pharmacological inhibition of the prostaglandin uptake transporter and EGFR and pharmacological and genetic modulation of EP2 receptor and HIF-1α. We found that iPGE2 increases HIF-1α expression through iEP2-dependent EGFR transactivation and that inhibition of any of the axis iEP2-EGFR-HIF-1α in cells treated with PGE2 or EP2 agonist results in prevention of the increase in PC3 cell proliferation, adhesion, migration, invasion and angiogenesis in vitro. Of note, PGE2 induced EP2 antagonist-sensitive DNA synthesis in nuclei isolated from PC3 cells, which indicates that they have functional EP2 receptors. These results suggest that PGE2-EP2 dependent intracrine mechanisms involving EGFR and HIF-1α play a role in PC.

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Abbreviations

BG:

Bromocresol green

EGFR:

Epidermal growth factor receptor

HIF-1α:

Hypoxia-inducible factor-1α

PGE2 :

Prostaglandin E2

PGT:

Prostaglandin transporter

VEGF-A:

Vascular endothelial growth factor-A

HRE:

HIF-responsive element

PC:

Prostate cancer

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Acknowledgments

We are grateful to Ono Pharmaceutical Co., Ltd. for kindly providing us with the EP agonists. This work was supported by Grant SAF2011-26838 from the Spanish Ministerio de Ciencia e Innovación. Ana Belén Fernández Martínez is the recipient of a postdoctoral fellowship from the Spanish Ministerio de Ciencia e Innovación.

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There are no conflicts of interest to disclose.

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  1. Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, 28871, Madrid, Spain

    Ana Belén Fernández-Martínez & Javier Lucio-Cazaña

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  1. Ana Belén Fernández-Martínez
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  2. Javier Lucio-Cazaña
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Correspondence to Ana Belén Fernández-Martínez.

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Fernández-Martínez, A.B., Lucio-Cazaña, J. Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells. Cell. Mol. Life Sci. 72, 3355–3373 (2015). https://doi.org/10.1007/s00018-015-1891-5

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