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

doi:10.1158/1078-0432.ccr-15-1275

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Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer

Journal article

Open access

Peer reviewed

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, …

Clinical cancer research, Vol.22(7), pp.1713-1724

04/01/2016

DOI: 10.1158/1078-0432.ccr-15-1275

PMCID: PMC4818718

PMID: 26581245

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Abstract

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.

Phosphorylation

Apoptosis - drug effects

Humans

Ovarian Neoplasms - pathology

Stress, Physiological

JNK Mitogen-Activated Protein Kinases - metabolism

Ovarian Neoplasms - genetics

Female

Transcription, Genetic

Antineoplastic Agents - pharmacology

Ovarian Neoplasms - metabolism

Gene Expression Regulation, Neoplastic - drug effects

Ovarian Neoplasms - drug therapy

Disease Models, Animal

Dual Specificity Phosphatase 1 - genetics

Promoter Regions, Genetic

Adrenergic Agents - pharmacology

Receptors, Adrenergic, beta-2 - metabolism

Xenograft Model Antitumor Assays

Animals

Signal Transduction - drug effects

Models, Biological

Proto-Oncogene Proteins c-jun - metabolism

Cell Line, Tumor

Dual Specificity Phosphatase 1 - metabolism

Mice

Catecholamines - pharmacology

Details

Title: Subtitle: Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer
Creators: Yu Kang - Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Archana S Nagaraja - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Guillermo N Armaiz-Pena - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Piotr L Dorniak - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Wei Hu - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Rajesha Rupaimoole - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Tao Liu - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Kshipra M Gharpure - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Rebecca A Previs - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Jean M Hansen - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Cristian Rodriguez-Aguayo - Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
Cristina Ivan - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas
Prahlad Ram - Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Vasudha Sehgal - Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Gabriel Lopez-Berestein - Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
Susan K Lutgendorf - Departments of Psychology, Obstetrics and Gynecology, and Urology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Steven W Cole - Department of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles School of Medicine, UCLA Molecular Biology Institute, and Norman Cousins Center, Los Angeles, California
Anil K Sood - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. asood@mdanderson.org
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.22(7), pp.1713-1724
DOI: 10.1158/1078-0432.ccr-15-1275
PMID: 26581245
PMCID: PMC4818718
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Publisher: United States
Grant note: T32 CA101642 / NCI NIH HHS CA104825 / NCI NIH HHS R01 CA104825 / NCI NIH HHS R01 CA177909 / NCI NIH HHS P50 CA098258 / NCI NIH HHS R01 CA109298 / NCI NIH HHS CA098258 / NCI NIH HHS CA 109298 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA140933 / NCI NIH HHS CA140933 / NCI NIH HHS P30 CA016672 / NCI NIH HHS P50 CA083639 / NCI NIH HHS R01 CA193249 / NCI NIH HHS
Language: English
Date published: 04/01/2016
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Urology
Record Identifier: 9984002444602771

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