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PGE2 modulates the transcriptional activity of ERRa in prostate stromal cells

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Abstract

The regulation of the transcriptional activity of the estrogen receptor-related receptor a (ERRa) has not yet been clearly documented. Aromatase is a direct target gene of ERRa, and we previously reported that prostaglandin E2 (PGE2) increased the expression of ERRa in the prostate stromal cell line WPMY-1, which ultimately promoted estradiol production by enhancing aromatase gene transcription. Here, we show that PGE2 also affects aromatase expression by regulating ERRa transcriptional activity in prostate stromal cells. When the cells were cultured in serum-free medium, the expression of aromatase was not proportional to the ERRa protein level, if no other stimulation occurred, indicating the absence of a factor that activates ERRa. PGE2 could upregulate aromatase and ERRa response element (ERRE)-reporter expression and also enhance ERRa phosphorylation and nuclear localization. PGE2 functions through the PGE2 receptors (EP) 2 and EP4, which couple to adenylate cyclase. The activation of adenylate cyclase with Forskolin mimicked the PGE2-mediated enhancement of extracellular signal-regulated kinase (ERK) phosphorylation and ERRa target gene expression. Experiments using specific signaling pathway inhibitors showed that both phosphatidylinositol 3-kinase (PI3K) and ERK are involved in ERRa activation, and the PI3K inhibitor was shown to abolish ERK activation. Our results suggest that PGE2 is a modulator of ERRa transcriptional activity. Furthermore, PGE2 activates the EP2/EP4-cAMP-PI3K-ERK signaling pathway, which enhanced ERRa transcriptional potentiality by increasing ERRa phosphorylation and nuclear translocation, subsequently promoting the expression of its target genes, such as aromatase.

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Acknowledgments

We thank Prof. Vanacker (Université de Lyon, France) for the gift of ERRa expression plasmid and ERRE luciferase reporter plasmid. This research was funded by National Natural Science Foundation of China (No. 81370859), National Basic Research Programs (973 Programs, No. 2010CB945003), State Key Development Program for Basic Research of China (973 program, No. 2012CB723500), Tianjin Municipal Science and Technology Commission (No. 12ZCDZSY17000), the 111 Project (No. B08011).

Conflict of interest

The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

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Authors and Affiliations

  1. College of Life Sciences and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China

    Zhaochen Ning, Xiaoling Du, Ju Zhang, Hui Yuan, Linlin Wang & Jiandang Shi

  2. Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China

    Kuo Yang

  3. Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China

    Lin Miao & Yan Zhu

  4. Department of Urology, Innsbruck Medical University, 6020, Innsbruck, Austria

    Helmut Klocker

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  1. Zhaochen Ning
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Correspondence to Ju Zhang or Jiandang Shi.

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Supplement Fig. 1

a Upper panel ERRa expression in the vector or ERRa expression plasmid stably transfected WPMY-1 cells. Lower panel the stable ERRa-transfected WPMY-1 cells were treated with PGE2 (1 μM), Butaprost (5 μM), Cay10580 (5 μM), or Forskolin (1 μM). After 8 h, the protein was extracted, and western blot analysis was performed. b PGE2 increases the phosphorylation of AKT in WPMY-1 cells. WPMY-1cells were treated with PGE2 (1 μM). After 30 min, whole cell lysates were extracted, and Western blot analysis was performed using antibodies against phosphor or total AKT (DOC 396 kb)

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Ning, Z., Du, X., Zhang, J. et al. PGE2 modulates the transcriptional activity of ERRa in prostate stromal cells. Endocrine 47, 901–912 (2014). https://doi.org/10.1007/s12020-014-0261-7

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