title: Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis.
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.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Nagaraja
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Dorniak
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Sadaoui
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of General Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Armaiz-Pena
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Allen
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Gharpure
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zand
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Previs
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Hansen
authors.affiliation: Center for RNAi and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Center for RNAi and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of General Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: Center for RNAi and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Psychology, Obstetrics and Gynecology, and Urology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Lutgendorf
authors.affiliation: 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.
authors.forename: S W
authors.initials: SW
authors.lastname: Cole
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNAi and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009638:Norepinephrine / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000071876:Prostaglandin-E Synthases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051546:Cyclooxygenase 2; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D009638:Norepinephrine