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

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 tum...

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Bibliographic Details
Published in:Oncogene 2016-05, Vol.35 (18), p.2390-2397
Main Authors: Nagaraja, A S, Dorniak, P L, Sadaoui, N C, Kang, Y, Lin, T, Armaiz-Pena, G, Wu, S Y, Rupaimoole, R, Allen, J K, Gharpure, K M, Pradeep, S, Zand, B, Previs, R A, Hansen, J M, Ivan, C, Rodriguez-Aguayo, C, Yang, P, Lopez-Berestein, G, Lutgendorf, S K, Cole, S W, Sood, A K
Format: Article
Language:English
Subjects:
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Animals
Apoptosis
Catecholamines
Cell Biology
Cell Line, Tumor
Cyclooxygenase 2 - deficiency
Cyclooxygenase 2 - genetics
Dinoprostone - biosynthesis
Female
Gene Silencing
Human Genetics
Humans
Internal Medicine
Medicine
Medicine & Public Health
Metastases
Metastasis
Mice
Neoplasm Metastasis
NF-κB protein
Norepinephrine
Norepinephrine - metabolism
Oncology
original-article
Ovarian cancer
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Prostaglandin E2
Prostaglandin-E Synthases - metabolism
Proteins
Signal Transduction
Tumors
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.302