Adrenergic stimulation of DUSP1 impairs chemotherapy response in ovarian cancer

Yu Kang, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, Piotr L. Dorniak, Wei Hu, Rajesha Rupaimoole, Tao Liu, Kshipra M. Gharpure, Rebecca A. Previs, Jean M. Hansen, Cristian Rodriguez-Aguayo, Cristina Ivan, Prahlad Ram, Vasudha Sehgal, Gabriel Lopez-Berestein, Susan K. Lutgendorf, Steven W. Cole, Anil K. Sood

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1713-1724
Number of pages12
JournalClinical Cancer Research
Volume22
Issue number7
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Research Animal Support Facility
  • Cytogenetics and Cell Authentication Core

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