Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells.
Interleukin (IL)-6, a multifunctional regulator of immune response, hematopoiesis, and acute phase reactions, has also been shown to regulate cancer cell proliferation. We have investigated IL-6 signaling pathways and cellular responses in the T47D breast carcinoma cell line. The IL-6-type cytokines, IL-6 and oncostatin M, simultaneously inhibited cell proliferation and ... increased cell migration. In T47D cells, IL-6 stimulated the activation of Janus-activated kinase 1 tyrosine kinase and signal transducers and activators of transcription (STAT) 1 and STAT3 transcription factors. Expression of dominant negative STAT3 in the cells strongly reduced IL-6-mediated growth inhibition but did not prevent IL-6-induced cell migration. IL-6 treatment led to activation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase (PI3K) pathways. Inhibition of MAPK or PI3K activity reversed IL-6- and oncostatin M-stimulated migration. Because cross-talk between cytokine receptors and members of the ErbB family of receptor tyrosine kinases has been described previously, we have examined their interaction in T47D cells. Down-regulation of ErbB receptor activity, through the use of specific pharmacological inhibitors or dominant negative receptor constructs, revealed that IL-6-induced MAPK activation was largely dependent on epidermal growth factor (EGF) receptor activity, but not on ErbB-2 activity. Using a monoclonal antibody that interferes with EGF receptor-ligand interaction, we have shown that in T47D cells, IL-6 cooperates with an EGF receptor autocrine activity loop for signaling through the MAPK and PI3K pathways and for cell migration. Both the tyrosine phosphatase SHP-2 and the multisubstrate docking molecule Gab1, which are potential links between IL-6 and the MAPK/PI3K pathways, were constitutively associated with the active EGF receptor. On IL-6 stimulation, SHP-2 and Gab1 were recruited to the gp130 subunit of the IL-6 receptor and tyrosine phosphorylated, allowing downstream signaling to the MAPK and PI3K pathways. Thus, in T47D breast carcinoma cells, IL-6 acts in synergy with EGF receptor autocrine activity to signal through the MAPK/PI3K pathways. Cooperation between IL-6 and the EGF receptor in T47D breast carcinoma cells illustrates how a combination of multiple stimuli, either exogenous or endogenous, may result in synergistic cellular responses.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Breast Neoplasms, Cell Division, Cell Movement, DNA-Binding Proteins, Enzyme Activation, ErbB Receptors, Humans, Interleukin-6, Intracellular Signaling Peptides and Proteins, Janus Kinase 1, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase Kinases, Oncostatin M, Peptides, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Receptor, ErbB-2, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Tumor Cells, Cultured, Tyrosine
Adaptor Proteins, Signal Transducing, Breast Neoplasms, Cell Division, Cell Movement, DNA-Binding Proteins, Enzyme Activation, ErbB Receptors, Humans, Interleukin-6, Intracellular Signaling Peptides and Proteins, Janus Kinase 1, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase Kinases, Oncostatin M, Peptides, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Receptor, ErbB-2, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Tumor Cells, Cultured, Tyrosine
Cancer Res.
Date: Jan. 01, 2001
PubMed ID: 11196191
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