TY - JOUR
T1 - Adrenergic stimulation of DUSP1 impairs chemotherapy response in ovarian cancer
AU - Kang, Yu
AU - Nagaraja, Archana S.
AU - Armaiz-Pena, Guillermo N.
AU - Dorniak, Piotr L.
AU - Hu, Wei
AU - Rupaimoole, Rajesha
AU - Liu, Tao
AU - Gharpure, Kshipra M.
AU - Previs, Rebecca A.
AU - Hansen, Jean M.
AU - Rodriguez-Aguayo, Cristian
AU - Ivan, Cristina
AU - Ram, Prahlad
AU - Sehgal, Vasudha
AU - Lopez-Berestein, Gabriel
AU - Lutgendorf, Susan K.
AU - Cole, Steven W.
AU - Sood, Anil K.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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 norepinephrineinduced 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.
AB - 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 norepinephrineinduced 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.
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U2 - 10.1158/1078-0432.CCR-15-1275
DO - 10.1158/1078-0432.CCR-15-1275
M3 - Article
C2 - 26581245
AN - SCOPUS:84964335150
SN - 1078-0432
VL - 22
SP - 1713
EP - 1724
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -