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

Departments of ¹ Gynecologic Oncology, ² Surgical Oncology, ³ Cancer Biology, and ⁴ Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁵ Division of Hematology-Oncology, Department of Medicine, University of California at Los Angeles School of Medicine, Los Angeles, California; ⁶ Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri; and ⁷ Department of Psychology, University of Iowa, Iowa City, Iowa

Requests for reprints: Anil K. Sood, Departments of Gynecologic Oncology and Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1155 Herman Pressler, CPB6.3244, Unit 1362, Houston, TX 77230-1439. Phone: 713-745-5266; Fax: 713-792-7586; E-mail: asood{at}mdanderson.org.

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 ß1- and ß2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the receptor blockers prazosin (1) and/or yohimbine (2). 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 ß1/ß2-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. [Cancer Res 2007;67(21):10389–96]