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 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.
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
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