Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 1; pp. 383 - 391
• Main Authors: BADACHE, Ali, HYNES, Nancy E
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2001
• Subjects: Adaptor Proteins, Signal Transducing; Biological and medical sciences; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Division - drug effects; Cell Movement - drug effects; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Humans; Interleukin-6 - pharmacology; Interleukin-6 - physiology; Intracellular Signaling Peptides and Proteins; Janus Kinase 1; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinase Kinases - physiology; Molecular and cellular biology; Oncostatin M; Peptides - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-Kinases - physiology; Phosphoproteins - metabolism; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - metabolism; Protein-Tyrosine Kinases - metabolism; Protein-Tyrosine Kinases - physiology; Receptor, Epidermal Growth Factor - physiology; Receptor, ErbB-2 - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; STAT3 Transcription Factor; Trans-Activators - metabolism; Trans-Activators - physiology; Tumor Cells, Cultured; Tyrosine - metabolism; Cell proliferation; Tyrosine; Carcinoma; Enzyme; Transferases; Cytokine; Tissue specificity; Malignant tumor; Carcinogenesis; In vitro; 1-Phosphatidylinositol 3-kinase; Interleukin 6; Mammary gland diseases; Signal transduction; Association; Epidermal growth factor; Polypeptide; Protein kinase; C-Onc gene; Established cell line; Mammary gland; Growth factor; Biological receptor
• ISSN: 0008-5472; 1538-7445

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.