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Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co- regulator PLAS3

  1. Author:
    Wang, L. H.
    Yang, X. Y.
    Mihalic, K.
    Xiao, W. H.
    Li, D. P.
    Farrar, W. L.

  2. Author Address

    Sci Applicat Int Corp, Intramural Res Support Program, NCI, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, NCI, Frederick, MD 21702 USA. NCI, Div Basic Sci, Mol Immunoregulat Lab, Cytokine Mol Mech Sect, Frederick, MD 21702 USA. Wang LH Sci Applicat Int Corp, Intramural Res Support Program, NCI, Frederick, MD 21702 USA.
    1. Year: 2001
  2. Journal: Journal of Biological Chemistry
    1. 276
    2. 34
    3. Pages: 31839-31844
  4. Type of Article: Article
  1. Abstract:

    Estrogen receptors (ERs)(1) highly expressed by multiple myeloma (NM) cells and stimulation of estrogenic ligands leads to cell apoptosis. Interleukin (IL)-6 is a major growth factor in the pathogenesis of MM. However, little is known concerning the molecular consequences of ER activation on IL-6-regulated AM cell growth. Here we show that the ER agonist 17 beta - estradiol completely abolished IL-6-inducible AM cell proliferation. By contrast, the ER antagonist ICI 182,780 overcame the inhibitory effect of estrogen. Estrogen blocked STAT3 DNA binding and transactivation but failed to affect the mRNA expression of IL-6 receptor chains or activation of JAK2 and STAT3. Estrogen-activated ER did not associate directly with STAT3. Estrogen induced the mRNA expression of PIAS3 ((p) under bar rotein (i) under bar nhibitor of (a) under bar ctivated (S) under bar TAT (3) under bar) and increased PIAS3 physical association with STAT3, suggesting a possible mechanism of STAT3 inhibition requiring PIAS3 as a co-regulator modulating the cross-talk between ER and STAT3. These data directly demonstrate STAT3 to be a molecular participant in ER inhibition of the IL-6 signaling pathway in human AM cells and provides the molecular basis for the potential use of estrogenic ligands in the treatment of AM or other tumors where IL-6 has an autocrine or paracrine role.

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