Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis.
Title | Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Nagaraja AS, Dorniak PL, Sadaoui NC, Kang Y, Lin T, Armaiz-Pena G, Wu SY, Rupaimoole R, Allen JK, Gharpure KM, Pradeep S, Zand B, Previs RA, Hansen JM, Ivan C, Rodriguez-Aguayo C, Yang P, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK |
Journal | Oncogene |
Volume | 35 |
Issue | 18 |
Pagination | 2390-7 |
Date Published | 2016 May 5 |
ISSN | 1476-5594 |
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. |
DOI | 10.1038/onc.2015.302 |
Alternate Journal | Oncogene |
PubMed ID | 26257064 |
PubMed Central ID | PMC4749473 |
Grant List | P30 CA016672 / CA / NCI NIH HHS / United States P50 CA083639 / CA / NCI NIH HHS / United States P50 CA098258 / CA / NCI NIH HHS / United States R01 CA104825 / CA / NCI NIH HHS / United States R01 CA109298 / CA / NCI NIH HHS / United States R01 CA116778 / CA / NCI NIH HHS / United States R01 CA140933 / CA / NCI NIH HHS / United States R01 CA177909 / CA / NCI NIH HHS / United States R37 AG033590 / AG / NIA NIH HHS / United States T32 CA101642 / CA / NCI NIH HHS / United States UH2 TR000943 / TR / NCATS NIH HHS / United States |