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

A S Nagaraja | P L Dorniak | N C Sadaoui | Y Kang | T Lin | G Armaiz-Pena | S Y Wu | R Rupaimoole | J K Allen | K M Gharpure | S Pradeep | B Zand | R A Previs | J M Hansen | C Ivan | C Rodriguez-Aguayo | P Yang | G Lopez-Berestein | S K Lutgendorf | S W Cole | A K Sood
Oncogene | 2016

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.

Pubmed ID: 26257064

Research resources used in this publication

None found

Antibodies used in this publication

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: T32 CA101642
  • Agency: NCI NIH HHS, United States
    Id: R01 CA116778
  • Agency: NCI NIH HHS, United States
    Id: P30 CA016672
  • Agency: NCATS NIH HHS, United States
    Id: UH2 TR000943
  • Agency: NCI NIH HHS, United States
    Id: R01 CA177909
  • Agency: NCI NIH HHS, United States
    Id: R01 CA109298
  • Agency: NCI NIH HHS, United States
    Id: P50 CA098258
  • Agency: NCI NIH HHS, United States
    Id: R01 CA193249
  • Agency: NCI NIH HHS, United States
    Id: R01 CA104825
  • Agency: NCI NIH HHS, United States
    Id: P50 CA083639
  • Agency: NIA NIH HHS, United States
    Id: R37 AG033590
  • Agency: NIA NIH HHS, United States
    Id: P30 AG017265
  • Agency: NCI NIH HHS, United States
    Id: R01 CA140933
  • Agency: NCI NIH HHS, United States
    Id: HHSN261200800001E

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