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 PIAS3

• Published in: The Journal of biological chemistry 2001-08, Vol.276 (34), p.31839-31844
• Main Authors: Wang, L H, Yang, X Y, Mihalic, K, Xiao, W, Li, D, Farrar, W L
• Format: Article
• Language: English
• Subjects: Base Sequence; Carrier Proteins - physiology; DNA - metabolism; DNA Primers; DNA-Binding Proteins - metabolism; Estradiol - pharmacology; estrogen receptors; Humans; Interleukin-6 - physiology; multiple myeloma; Multiple Myeloma - pathology; PIAS3 protein; Receptor Cross-Talk - physiology; Receptors, Estrogen - agonists; Receptors, Estrogen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor; Trans-Activators - metabolism; Transcriptional Activation - drug effects; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M105185200

Estrogen receptors (ERs) 1 highly expressed by multiple myeloma (MM) 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 MM cell growth. Here we show that the ER agonist 17β-estradiol completely abolished IL-6-inducible MM 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 rotein i nhibitor of a ctivated S TAT 3 ) 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 MM cells and provides the molecular basis for the potential use of estrogenic ligands in the treatment of MM or other tumors where IL-6 has an autocrine or paracrine role.