title: STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence.
abstract: Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-β (TGF-β) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-β/SMAD signaling by expressing a dominant-negative TGF-β receptor, treating with a TGF-β receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSM-induced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.
authors.affiliation: a Department of Pathology , School of Medicine, Case Western Reserve University , Cleveland , OH , USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Bryson
authors.affiliation: a Department of Pathology , School of Medicine, Case Western Reserve University , Cleveland , OH , USA.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Junk
authors.affiliation: a Department of Pathology , School of Medicine, Case Western Reserve University , Cleveland , OH , USA.
authors.forename: Rocky
authors.initials: R
authors.lastname: Cipriano
authors.affiliation: a Department of Pathology , School of Medicine, Case Western Reserve University , Cleveland , OH , USA.|b Case Comprehensive Cancer Center , Case Western Reserve University , Cleveland , OH , USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Jackson
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D006801:Humans; D042361:Mammary Glands, Human / Q000473:pathology; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D053683:Oncostatin M / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; D051901:Smad4 Protein; D053683:Oncostatin M
keywords: MYC; Oncostatin M; SMAD3; STAT3; cytokine; epithelial-mesenchymal transition; human mammary epithelial cells; invasion; senescence; transforming growth factor-β