Neuroendocrine Modulation of Signal Transducer and Activator of Transcription-3 in Ovarian Cancer

Charles N LANDEN; Yvonne G LIN; Susan K LUTGENDORF; Cherylyn A SAVARY; Angela M SANGUINO; Gabriel LOPEZ-BERESTEIN; Steve W COLE; Anil K SOOD; Guillermo N ARMAIZ PENA; Pamela D DAS; Jesusa M AREVALO; Aparna A KAMAT; Liz Y HAN; Nicholas B JENNINGS; Whitney A SPANNUTH; Premal H THAKER

doi:10.1158/0008-5472.CAN-07-0858

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Neuroendocrine Modulation of Signal Transducer and Activator of Transcription-3 in Ovarian Cancer

Journal article

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Neuroendocrine Modulation of Signal Transducer and Activator of Transcription-3 in Ovarian Cancer

Charles N LANDEN, Yvonne G LIN, Susan K LUTGENDORF, Cherylyn A SAVARY, Angela M SANGUINO, Gabriel LOPEZ-BERESTEIN, Steve W COLE, Anil K SOOD, Guillermo N ARMAIZ PENA, Pamela D DAS, …

Cancer research (Chicago, Ill.), Vol.67(21), pp.10389-10396

2007

DOI: 10.1158/0008-5472.CAN-07-0858

PMID: 17974982

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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.

Antineoplastic Agents

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Biological and medical sciences

Medical sciences

Pharmacology. Drug treatments

Details

Title: Subtitle: Neuroendocrine Modulation of Signal Transducer and Activator of Transcription-3 in Ovarian Cancer
Creators: Charles N LANDEN - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Yvonne G LIN - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Susan K LUTGENDORF - Department of Psychology, University of Iowa, Iowa City, Iowa, United States
Cherylyn A SAVARY - Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Angela M SANGUINO - Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Gabriel LOPEZ-BERESTEIN - Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Steve W COLE - Division of Hematology-Oncology, Department of Medicine, University of California at Los Angeles School of Medicine, Los Angeles, California, United States
Anil K SOOD - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Guillermo N ARMAIZ PENA - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Pamela D DAS - Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Jesusa M AREVALO - Division of Hematology-Oncology, Department of Medicine, University of California at Los Angeles School of Medicine, Los Angeles, California, United States
Aparna A KAMAT - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Liz Y HAN - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Nicholas B JENNINGS - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Whitney A SPANNUTH - Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Premal H THAKER - Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, United States
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.67(21), pp.10389-10396
DOI: 10.1158/0008-5472.CAN-07-0858
PMID: 17974982
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: American Association for Cancer Research; Philadelphia, PA
Language: English
Date published: 2007
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Urology
Record Identifier: 9984065884702771

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