Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer.

TitleAdrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsKang Y, Nagaraja AS, Armaiz-Pena GN, Dorniak PL, Hu W, Rupaimoole R, Liu T, Gharpure KM, Previs RA, Hansen JM, Rodriguez-Aguayo C, Ivan C, Ram P, Sehgal V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK
JournalClin Cancer Res
Volume22
Issue7
Pagination1713-24
Date Published2016 Apr 1
ISSN1078-0432
Abstract

PURPOSE: Chronic adrenergic activation has been shown to associate with adverse clinical outcomes in cancer patients, but the underlying mechanisms are not well understood. The focus of the current study was to determine the functional and biologic effects of adrenergic pathways on response to chemotherapy in the context of ovarian cancer.

EXPERIMENTAL DESIGN: Increased DUSP1 production by sympathetic nervous system mediators (e.g., norepinephrine) was analyzed by real-time quantitative RT-PCR and by Western blotting. In vitro chemotherapy-induced cell apoptosis was examined by flow cytometry. For in vivo therapy, a well-characterized model of chronic stress was used.

RESULTS: Catecholamines significantly inhibited paclitaxel- and cisplatin-induced apoptosis in ovarian cancer cells. Genomic analyses of cells treated with norepinephrine identified DUSP1 as a potential mediator. DUSP1 overexpression resulted in reduced paclitaxel-induced apoptosis in ovarian cancer cells compared with control; conversely, DUSP1 gene silencing resulted in increased apoptosis compared with control cells. DUSP1 gene silencing in vivo significantly enhanced response to paclitaxel and increased apoptosis. In vitro analyses indicated that norepinephrine-induced DUSP1 gene expression was mediated through ADRB2 activation of cAMP-PLC-PKC-CREB signaling, which inhibits JNK-mediated phosphorylation of c-Jun and protects ovarian cancer cells from apoptosis. Moreover, analysis of The Cancer Genome Atlas data showed that increased DUSP1 expression was associated with decreased overall (P= 0.049) and progression-free (P= 0.0005) survival.

CONCLUSIONS: These findings provide a new understanding of the mechanisms by which adrenergic pathways can impair response to chemotherapy and have implications for cancer management.

DOI10.1158/1078-0432.CCR-15-1275
Alternate JournalClin. Cancer Res.
PubMed ID26581245
PubMed Central IDPMC4818718
Grant ListCA 109298 / CA / NCI NIH HHS / United States
CA098258 / CA / NCI NIH HHS / United States
CA104825 / CA / NCI NIH HHS / United States
CA140933 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
P50 CA083639 / 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 CA140933 / CA / NCI NIH HHS / United States
R01 CA177909 / CA / NCI NIH HHS / United States
T32 CA101642 / CA / NCI NIH HHS / United States
T32 CA101642 / CA / NCI NIH HHS / United States