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Clin Cancer Res. 2016 Apr 1;22(7):1713-24. doi: 10.1158/1078-0432.CCR-15-1275. Epub 2015 Nov 18.

Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer.

Author information

1
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.
2
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
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.
4
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.
5
Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Departments of Psychology, Obstetrics and Gynecology, and Urology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
7
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.
8
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.

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 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.

PMID:
26581245
PMCID:
PMC4818718
DOI:
10.1158/1078-0432.CCR-15-1275
[Indexed for MEDLINE]
Free PMC Article

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