Abstract
The interleukin-6 cytokine oncostatin M (OSM) induces potent growth-inhibitory and morphogenic responses in several different tumor cell types, highlighting the importance of OSM signaling mechanisms as targets for therapeutic intervention. The specific molecular pathways involved are not well understood, as OSM can signal through two separate heterodimeric receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) alpha and gp130/OSM receptor beta (OSMRbeta). In this investigation, we used a LIFR antagonist to help resolve signaling responses and identify patterns of gene expression elicited by the different receptor complexes. OSM-induced biological effects on breast tumor-derived cell lines were specifically mediated through the gp130/OSMRbeta complex. Each cytokine tested exhibited differential signaling capability and manifested both shared and unique patterns of gene activation, emphasizing compositional differences in activator protein-1 transcription factor activity and expression. In particular, OSM strongly activated the c-Jun NH(2)-terminal kinase (JNK) serine/threonine kinase and downstream components, including activating transcription factor (ATF)/cyclic AMP-responsive element binding protein family member, ATF3. JNK/stress-activated protein kinase kinase inhibition abrogated cell morphogenesis induced by OSM, indicating an important role for this pathway in OSM specificity. These findings identify a core signaling/transcriptional mechanism specific to the OSMRbeta in breast tumor cells.
Highlights
Receptor-mediated signal transduction pathways are a major target for anticancer drug development [1]
The aim of this study was to delineate the molecular pathways involved in the cellular responses of breast tumor cells to the cytostatic cytokine oncostatin M (OSM)
Studies using the receptor-specific antagonist leukemia inhibitory factor (LIF)-05 revealed that the characteristic functions of OSM are executed by signaling through the gp130/OSMRh complex and not by the gp130/LIFRa complex, which has a broader ligand specificity [5]
Summary
Receptor-mediated signal transduction pathways are a major target for anticancer drug development [1]. Suppression of tumor cell growth can be achieved by inhibiting pathways that activate cell multiplication or by activating pathways that inhibit cell multiplication. Molecular definition of the pathways that negatively regulate cell multiplication in tumor cells would open up new prospects for the manipulation of tumor cell growth. The characterization of negative growth-regulatory signal transduction pathways has been greatly aided by the identification of ligands that suppress tumor cell growth. We analyze the molecular mechanisms of signal transduction mediated by the cytostatic cytokine oncostatin M (OSM), which result in the suppression of tumor cell proliferation. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)
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