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- W2597156827 abstract "AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA2148 Objectives : Chronic stress is associated with cancer growth and progression, but the underlying mechanisms of this association are incompletely understood. We examined the role of STAT3, a transcription factor affecting many oncogenic pathways, in mediating invasion and metastasis pathways induced by the stress-associated hormones norepinephrine (NE), epinephrine (Epi), and isoproterenol (Iso).Methods : In vitro, the epithelial ovarian cancer cell lines SKOV3 and EG were exposed to increasing concentrations of NE, Epi, or Iso, with and without beta-blockers (propanolol), alpha1- or alpha-2 blockers (prazosin or yohimbine). STAT3 activation, localization, and DNA binding were measured by Western blot, immunohistochemistry, and the Electrophoretic Mobility Shift Assay (EMSA). MMP-2 and MMP-9 levels were measured by ELISA. In vivo, orthotopic ovarian tumors were examined for patterns of metastasis (by inspection) and MMP-2 and MMP-9 expression (by immunohistochemistry) in mice subjected to chronic beta agonists, with and without liposomal STAT3-specific siRNA.Results : NE, Epi and Iso induce phosphorylation of STAT3, with subsequent translocation to the nucleus and DNA binding, in a dose-dependent fashion in both SKOV3 and EG cell lines. STAT3 phosphorylation was inhibited by propanolol and by KT5720 (PKA inhibitor); but not by prazocin, yohimbime, or anti-IL-6 antibody. Cells stimulated with Iso had increased MMP-2 (by 2.4-fold) and MMP-9 (1.9-fold) production, but this increase was abrogated by STAT3 inhibition with anti-STAT3 siRNA. In mice stressed with daily Iso, tumors were significantly more invasive, and had increased MMP-2 and MMP-9 expression. However, downregulation of STAT3 with liposomal siRNA completely abrogated the increased invasiveness and MMP-2 and -9 induction by Iso.Conclusions : Stress hormones acting through beta-adrenergic receptors induce STAT3 activation, with subsequent transport to the nucleus and DNA binding. Through STAT3, these hormones increase MMP-2 and MMP-9 expression, and tumor invasiveness. This pathway may play an important role in malignant progression, with particular importance in conditions of chronic stress." @default.
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- W2597156827 date "2007-05-01" @default.
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- W2597156827 title "STAT3 as a mediator of neuroendocrine-induced invasion in ovarian cancer" @default.
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