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Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis

Oncogene volume 35, pages 2390–2397 (2016)Cite this article

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Abstract

Adrenergic stimulation adversely affects tumor growth and metastasis, but the underlying mechanisms are not well understood. Here, we uncovered a novel mechanism by which catecholamines induce inflammation by increasing prostaglandin E2 (PGE2) levels in ovarian cancer cells. Metabolic changes in tumors isolated from patients with depression and mice subjected to restraint stress showed elevated PGE2 levels. Increased metabolites, PTGS2 and PTGES protein levels were found in Skov3-ip1 and HeyA8 cells treated with norepinephrine (NE), and these changes were shown to be mediated by ADRB2 receptor signaling. Silencing PTGS2 resulted in significantly decreased migration and invasion in ovarian cancer cells in the presence of NE and decreased tumor burden and metastasis in restraint stress orthotopic models. In human ovarian cancer samples, concurrent increased ADRB2, PTGS2 and PTGES expression was associated with reduced overall and progression-free patient survival. In conclusion, increased adrenergic stimulation results in increased PGE2 synthesis via ADRB2–Nf-kB–PTGS2 axis, which drives tumor growth and metastasis.

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Acknowledgements

We thank the following for funding support: the United States National Institutes of Health (CA116778, CA104825, CA140933, CA109298, CPRIT RP140106, CPRIT RP110595, NIH CA 109298, P50CA083639, P50CA098258, AG017265, AG033590), NIH under Contract No. HHSN261200800001E and the Breast Cancer Research Foundation, the United States Department of Defense (OC073399, W81XWH-10-1-0158, and BC085265); the Marcus Foundation; the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer; the RGK Foundation; the Gilder Foundation; the Blanton-Davis Ovarian Cancer Research Program and the Betty Anne Asche Murray Distinguished Professorship (AKS). ASN is supported in part by the CPRIT Graduate Scholar Fellowship. KMG is supported by the Altman-Goldstein Discovery fellowship. SYW is supported by the Ovarian Cancer Research Fund, Inc., and by Cancer Prevention and Research Institute of Texas training grants (RP101502 and RP101489). RAP, BZ and JH are supported by the NCI-DHHS-NIH T32 training grant (T32 CA101642). We thank Laila Dahmoush at the University of Iowa for her help analyzing patient tumor slides. This research was supported by the National Cancer Institute Network on Biobehavioral Pathways in Cancer. We also thank Erica Goodoff at MD Anderson for help with scientific editing.

Author contributions

ASN and AKS conceived the project and designed the experiments. ASN, NCS, PLD, RAP, JKA, GA-P, JMH, SP, SYW, BZ and KMG carried out or participated in in vitro and in vivo experiments. CR-A and GL-B designed and prepared liposomes for in vivo studies. ASN and CI designed and performed computational analyses. TL and PY performed the Mass-spec analysis. ASN wrote the manuscript. ASN, PLD, SKL, SWC and AKS participated in manuscript preparation. All authors edited and approved the final manuscript.

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Authors and Affiliations

  1. Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA,

    A S Nagaraja, P L Dorniak, N C Sadaoui, Y Kang, G Armaiz-Pena, S Y Wu, R Rupaimoole, J K Allen, K M Gharpure, S Pradeep, B Zand, R A Previs, J M Hansen & A K Sood

  2. Department of General Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    T Lin & P Yang

  3. Center for RNAi and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Ivan, C Rodriguez-Aguayo, G Lopez-Berestein & A K Sood

  4. Department of Psychology, Obstetrics and Gynecology, and Urology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA

    S K Lutgendorf

  5. Department of Medicine, Division of Hematology-Oncology, Geffen School of Medicine, UCLA Molecular Biology Institute, Norman Cousins Center, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles

    S W Cole

  6. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A K Sood

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  1. A S Nagaraja
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Correspondence to A K Sood.

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Nagaraja, A., Dorniak, P., Sadaoui, N. et al. Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. Oncogene 35, 2390–2397 (2016). https://doi.org/10.1038/onc.2015.302

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