Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer.

TitleNeuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer.
Publication TypeJournal Article
Year of Publication2007
AuthorsLanden CN, Lin YG, Pena GNArmaiz, Das PD, Arevalo JM, Kamat AA, Han LY, Jennings NB, Spannuth WA, Thaker PH, Lutgendorf SK, Savary CA, Sanguino AM, Lopez-Berestein G, Cole SW, Sood AK
JournalCancer Res
Volume67
Issue21
Pagination10389-96
Date Published2007 Nov 1
ISSN1538-7445
KeywordsActive Transport, Cell Nucleus, Animals, Cell Line, Tumor, Cell Proliferation, Cyclic AMP-Dependent Protein Kinases, Epinephrine, Female, Humans, Interleukin-6, Matrix Metalloproteinases, Mice, Neoplasm Invasiveness, Norepinephrine, Ovarian Neoplasms, STAT3 Transcription Factor
Abstract

There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the beta1- and beta2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the alpha receptor blockers prazosin (alpha1) and/or yohimbine (alpha2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti-interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)-mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6-independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the beta1/beta2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3.

DOI10.1158/0008-5472.CAN-07-0858
Alternate JournalCancer Res.
PubMed ID17974982
Grant List5K12 HD00849 / HD / NICHD NIH HHS / United States
AI52737 / AI / NIAID NIH HHS / United States
CA109298 / CA / NCI NIH HHS / United States
CA110793 / CA / NCI NIH HHS / United States
P50 CA083639 / CA / NCI NIH HHS / United States