Oncostatin M (OSM) Cytostasis of Breast Tumor Cells: Characterization of an OSM Receptor β–Specific Kernel

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) A and gp130/OSM receptor B (OSMRB). 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 tumorderived cell lines were specifically mediated through the gp130/OSMRB 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 OSMRB in breast tumor cells. (Cancer Res 2006; 66(22): 10891-901)

CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts

“…This effect was associated with the activation of cytokine gene expression, suggesting that these cytokines may be involved in the P245-mediated inhibition of tumour growth (Pagliacci et al, 1993;Derynck et al, 2001;Shen et al, 2002;Underhill-Day and Heath, 2006). Interestingly, inhibition of breast cancer stem cells by TGF-b1 was reported recently (Tang et al, 2007) and TGF-b1 signalling is functional in CD44 þ breast cancer cells (Derynck et al, 2001).…”

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

“…19 OSM activates a gp130/ OSMRb receptor (OSMR) protein complex that is distinct from other IL-6 family co-receptors, which may account for the more potent OSM-induced senescence response. 26,76,77 OSMR complexes consisting of gp130/OSMRb heterodimers can activate STAT3, RAS-MAPK, and PI3K-AKT signaling, in addition to pathways not activated by other IL-6 family receptor complexes that signal via gp130/gp130 homodimers (STAT5, STAT6, AKT, and PKC-d). 19 In order to bypass the senescence program, developing cancer cells must dismantle cell cycle control by either inhibiting p16, pRb, and p53 or activating MYC (c-MYC).…”

“…22,25 Whereas OSM drives proliferation, epithelial-mesenchymal transition (EMT), invasion, and metastasis in breast cancer cells and transformed human mammary epithelial cells (HMEC), it engages senescence in normal and non-transformed HMEC. 13,[19][20][21][26][27][28][29][30][31][32][33][34] Senescence is an irreversible, proliferationinhibiting response that occurs in 2 steps: 1) reversible cell cycle arrest followed by 2) futile growth-induced gerogenic conversion, or geroconversion. [35][36][37] Moreover, senescence is a major tumorsuppressive mechanism that acts as an early barrier to thwart cancer development.…”

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

“…It was first identified as a secreted product of macrophage-like cells that inhibited proliferation of melanoma-, neuroblastoma-, and lung cancer-derived cell lines (2), and although it suppresses breast cancer cell proliferation (3), it has been suggested to support metastasis of breast cancer in the skeleton due to proosteoclastic activities (4) and to stimulate Kaposi's sarcoma (5). Studies in knock-out mice have shown that OSM supports hematopoiesis (6) and bone formation at the expense of adipogenesis (7), but it has also been implicated in pulmonary tissue fibrosis (8), cardiac disease and repair (9), prostate cancer (10), asthma (11), periodontal disease (12), and both rheumatoid and osteoarthritis (13).…”