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Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer.

Publication ,  Journal Article
Kang, Y; Nagaraja, AS; Armaiz-Pena, GN; Dorniak, PL; Hu, W; Rupaimoole, R; Liu, T; Gharpure, KM; Previs, RA; Hansen, JM; Rodriguez-Aguayo, C ...
Published in: Clin Cancer Res
April 1, 2016

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

April 1, 2016

Volume

22

Issue

7

Start / End Page

1713 / 1724

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transcription, Genetic
  • Stress, Physiological
  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Proto-Oncogene Proteins c-jun
  • Promoter Regions, Genetic
  • Phosphorylation
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
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Kang, Y., Nagaraja, A. S., Armaiz-Pena, G. N., Dorniak, P. L., Hu, W., Rupaimoole, R., … Sood, A. K. (2016). Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer. Clin Cancer Res, 22(7), 1713–1724. https://doi.org/10.1158/1078-0432.CCR-15-1275
Kang, Yu, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, Piotr L. Dorniak, Wei Hu, Rajesha Rupaimoole, Tao Liu, et al. “Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer.Clin Cancer Res 22, no. 7 (April 1, 2016): 1713–24. https://doi.org/10.1158/1078-0432.CCR-15-1275.
Kang Y, Nagaraja AS, Armaiz-Pena GN, Dorniak PL, Hu W, Rupaimoole R, et al. Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer. Clin Cancer Res. 2016 Apr 1;22(7):1713–24.
Kang, Yu, et al. “Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer.Clin Cancer Res, vol. 22, no. 7, Apr. 2016, pp. 1713–24. Pubmed, doi:10.1158/1078-0432.CCR-15-1275.
Kang 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. Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer. Clin Cancer Res. 2016 Apr 1;22(7):1713–1724.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

April 1, 2016

Volume

22

Issue

7

Start / End Page

1713 / 1724

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transcription, Genetic
  • Stress, Physiological
  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Proto-Oncogene Proteins c-jun
  • Promoter Regions, Genetic
  • Phosphorylation
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis