Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer

• Published in: Clinical cancer research Vol. 22; no. 7; pp. 1713 - 1724
• Main Authors: Kang, Yu, Nagaraja, Archana S, Armaiz-Pena, Guillermo N, Dorniak, Piotr L, Hu, Wei, Rupaimoole, Rajesha, Liu, Tao, Gharpure, Kshipra M, Previs, Rebecca A, Hansen, Jean M, Rodriguez-Aguayo, Cristian, Ivan, Cristina, Ram, Prahlad, Sehgal, Vasudha, Lopez-Berestein, Gabriel, Lutgendorf, Susan K, Cole, Steven W, Sood, Anil K
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Adrenergic Agents - pharmacology; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Catecholamines - pharmacology; Cell Line, Tumor; Disease Models, Animal; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Mice; Models, Biological; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Phosphorylation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-jun - metabolism; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction - drug effects; Stress, Physiological; Transcription, Genetic; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-1275

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